The list I posted was from the 1990 census; I couldn’t find such a list from the 2000, but, fortunately, others could.
Fresno had a mini-series set there called, hmmm, let me think, it’ll come to me in a minute. Oh, yeah, Fresno.
It looks like the winner is San Jose.
the original “saved by the bell” was set in indianapolis. somehow everyone moved together to bayside in the second incarnation of this execrable show.
Was there ever one in San Diego? CPO Sharkey perhaps?
Jacksonville is a banking and insurance town. Those are two gripping potential dramas, eh? We’ve got the ocean, but not worthy of a Baywatch scenario. There’s the Naval Air Station but none of the sexy airplanes fly outta there - no one cares about P-3s and S-3s. There are ships at Naval Station Mayport - can we try for a rehash of McHale’s Navy? Doubtful.
The land is being over-developed. It’s all flat and sand. Nothing exciting happens here. I live here and I don’t think I’d watch a show about anything local.
Does that answer your question?? 
Simon & Simon was set there. CPO Sharkey too, but S&S was probably the longest lasting San Diego series.
Was there ever a show set in Pittsburgh?
I hope whatever city it is will put up a welcome sign that says “Welcome to __________ The largest city without a TV show based in it.”
Maybe so, but didn’t The Creature From the Black Lagoon take at least part of his rampage through Jacksonville?
Pittsburgh: Mr. Belvedere
It’s all flat and sand pretty much describes all of Fla though, that’s not much of a Jacksonville only trait.
Houston had Houston Medical, which no one outside of Houston watched. Meh. Tulsa is definitely in the running, but what about Denver or St. Louis? Baltimore?
Baltimore: Homicide
I have been thinking about this since we were discussing it and I offer Malcolm in the Middle as taking place in the great state of Alabama.
Francis’ Military School was in Alabama. That was a major setting for the show. I think it should bump Bama from the list!
Hmm… anyone know of any shows set in Atlanta? Which isn’t a large city (by the numbers), but a pretty damned big metro area.
Designing Women
or Matlock…
… well, except that the question was largest city without a show, not largest state. Unless I misunderstood the OP, which wouldn’t be the first time …
So, are there any shows in Tampa, then?
I go by metro area, as no one really believes Boston is smaller than San Antonio. San Antonio’s city limits include suburban areas, where Boston’s do not.
No, you are correct, but there is a second list either in this thread or the other that has largest STATE without a show. That was listed as Alabama! I should have been more specific!