I’ve never read a comic book in my life. However, I do have a certain interest in superheroes etc. spurred mostly by recent video games and movies based on comics.
What do I start with? What issue do I start reading?
Assume price/availability aren’t factors.
Why don’t you drop by a local comic book store? Browse. Ask questions…
Yeah, I haven’t read in a while, but there’s too much to choose from. On the other hand, there’s too much to not find one you like. So go in and browse through titles and find a few that you can connect with. Then ask the sales guy about recent story lines that were good. I’d suggest reading a few graphic novels/collections before accepting the position you will find yourself in of waiting every week to read a damned comic book! not bitter
Which superhero-themed video games and movies have you liked? If we know that, we can point you to the comics that had particularly good treatments of the same characters.
You might want to consider some of the Ultimate series. Marvel comics started these a few years back. The idea was that some popular characters had become weighed down by over forty years of history so they basically restarted them as if they were new characters. So readers who are new to comics can read them without running across references to characters and events that happened in years past. Most of the Ultimate series have been collected into books which typically cover six or more original issues.
The Ultimate series is a good place to start as mentioned.
So is the suggestion of go and get what you liked in the games or the movies. If you liked the Fantastic Four movie or the Ghostrider movie then go get a couple of issues of those.
Or better yet, as mentioned, get a couple graphic novels they will have one storyline all wrapped up in one book. So if you liked the Fantastic Four movie go get a Fantastic Four graphic novel. One story arc and you will get a feel for the characters.
There are so many titles these days that there will be a couple that will be your cup of tea. Every couple months or so I go to my local shop and pick up a couple titles I have never read before just to try it out. Most times I never get another issue of a title but once in a while I find a gem and a new series to read.
I usually start with the beginning of the comic book. Otherwise, I wont understand what’s going on, and that’s just silly. You could skip the first few pages probably though, as they are mostly copyright and publisher info. Of course, this all assumes an American/European comic book and not Japanese manga, where the book ends at the beginning and begins at the ending.
Wow I sure like the sound of the Ultimate stuff. A fresh start sounds…refreshing.
Try JSA, from DC Comics.
WW2 era supers, & their heirs, literal & spiritual.
Well… The Ultimate Universe isn’t really that fresh any more.
Ultimate Spider-Man is at issue 108.
Ultimate X-Men is into the 80s.
Ultimate Fantastic Four is in its 40s.
The Ultimates is about to finish its second series. (13 issues each.)
Still worth reading them - more worth it than the equivalent mainline titles, IMO - but they have the better part of a decade of continuity built up themselves.
JSA is one of my favourite titles, but it is NOT a starter book. Not even vaguely. Most especially the current series, but no JSA series has been a particularly good starter series since the first run of All-Star Comics wrapped up in the 50s. It’s difficult to get more thoroughly tied up in continuity than a book that’s specifically about legacy and history within its universe.
I have a few comic books on the shelf but am still totally daunted by the big franchises so take this for what it’s worth… I really enjoyed Alan Moore’s “Top 10” - no characters or back story to be familiar with, but a nice superhero millieu. “The 49ers”, which is set in the same universe but an earlier era, is also really enjoyable.
If you liked the Hellboy movie, the Hellboy comics are also really, really accessible reads, and quite a bit of fun, although with a side order of deeply disturbing at times!
Invincible - pick up the first TPB or two, and then praise me. 
First off, you’ll probably want to buy trade paperbacks and not single issues. The singles are loaded with ads, flimsy, and not really worth much as collectibles. A trade paperback is going to be between six and twenty issues and should comprise a sizeable piece of a story arc.
For some collections you can actually get all of the issues bound in one book (like Watchmen or From Hell). Others you’ll end up paying between $15-$25 for each TPB and often needing to buy 6-10 TPBs to get a major story arc. The Sandman is 10 trades plus several miscellaneous chapters, and is worth every penny. Watchmen is also fantastic. Sin City trades are each their own story, but all of the stories intersect just a little bit. It’s not for everyone. If you like watching NBC’s Heroes you might enjoy X-Men. If you enjoy LOST you might like Y: the Last Man, which has not yet finished its run. If you like movies with an ensemble cast, like Sneakers or Serenity, you might enjoy Watchmen – fair warning, though, it’s not light reading by any stretch. Even the humor is dark and semi-political, and every helping comes with plenty of drama.
I agree with the other posters that you should go into a comics shop and ask around. Tell them you’d like to start with trades to get a feel for how the stories flow (and especially, how they end).
The cover.
Removed duplicate post
yes yes and yes to graphic novels, sandman and watchman!
Some superhero trade paperbacks I recommend:
Watchmen (usually considered the pinnacle of the genre)
Starman: Sins of the Father (the beginning of my all-time favorite series, and nine more volumes follow if you like it)
The Golden Age
The New Frontier (two separate volumes)
Supreme: The Story of the Year (if you have any interest in classic Superman)
Justice League: A New Beginning (essentially a sitcom with superheroes)
The Authority: Relentless (mad, widescreen action, violence, and gorgeous art that really shook up the industry)
Batman: Year One
Daredevil: Born Again
Catwoman: four TPBs written by Ed Brubaker (The Dark End of the Street, Crooked Little Town, Relentless, and Wild Ride)
Iron Man: Extremis
Batman: The Dark Knight Returns
She-Hulk: Single Green Female (lots of humor and heart)
Astonishing X-Men: Gifted (written by Joss Whedon, who made me care about the X-Men for the first time in almost 15 years)
I can come back with plenty of non-superhero recommendations too! Just don’t fall into the trap of buying single-issue comics. TPBs are the way to go. Don’t forget you can request them at your local public library via inter-library loan (or they may even have a selection already!)
Why not start simple?
The current runs of Superman and Detective Comics are both excellent.
P.S. Here are some things you SHOULDN’T read, unless you want to get turned off to superhero comics entirely:
Crisis on Infinite Earths. Written for knowledgable nerds and fanboys in the mid-'80s, the story has aged badly (and wasn’t that great to begin with) and depends on a LOT of familiarity with the complex DC Multiverse. Skip it, or at least revisit it later. A more recent “sequel,” Infinite Crisis, is equally impentetrable. Skip it. (IDENTITY Crisis, on the other hand, ain’t too bad, and serves as a decent jumping-on point to the DC Universe.)
Most DC Archives and Showcase editions and Marvel Masterworks and Essentials. These are reprints of old comics from the Golden and Silver Ages, either in color or black and white. A lot of the time, the stories seem corny, the dialogue is hokey, and as a new reader, you might not enjoy the older styles of art and coloring (even though you appreciate them more from a historical perspective later on). Trust me – when I was a kid, I thought Jack Kirby’s art sucked, but I was a big Rob Liefeld fan. This will all make sense later, but don’t get bogged down on the really old material until you develop a taste for the modern classics I mentioned above.