Fly out of Rome or Florence?

Everything depends on whether you want to go to Rome or not.
if not choose B

You don't sound like Rome is essential. I'd fly out of Florence. It's a short taxi ride to the airport (particularly for a very early flight or Sunday flight when there's no traffic). I've done both and far prefer Florence. It lets me enjoy my last night.

I would fly out of Florence, Plan B, as it is too time consuming to go to Rome and not really spend anytime in Rome.

Chances are that you won't get into or out of Venice or Florence airports without going through another European airport gateway city. There may only be a couple of flights from the U.S. seasonally, which means in the summer. I say this because many people fly out of Rome on a 6:00 a.m. flight and end up getting virtually no sleep the night before getting up for a 4:00 a.m. cab ride. The 6:00 a.m. flights take you to another European city where you'll be sitting until about noon. And then you fly to the U.S. and can again sit around waiting for connecting flights. I prefer to fly directly to the U.S. late morning, rather than sit around another European airport. Getting a good night's sleep certainly helps before a long flight.
And even a 1/2 day in Rome is worth taking in.

I had a conversation with an American airline. She said "no one flies out of Florence" which shocked me. There are good connections out of Pisa. you might consider that.

>>She said "no one flies out of Florence" which shocked me<< Florence airport is too small to take big jets that fly across the Atlantic; Pisa airport can handle bigger planes. But from the US, Pisa only gets US service in high season, a few days a week (and I think only from JFK). So, for most US residents, they have to change to fly to Florence, Pisa, or Bologna (Bologna, like Pisa, is not too far from Florence, although of course one has to figure in the time and money it takes to get from the origin airport to the actual destination). Sean: If it doesn't cost extra to fly out of Florence, then it doesn't make sense to spend time and money getting to Rome just to catch a flight. Focus on Tuscany destinations this time. I'm sure on a future trip, flying out of Rome will either be more convenient or less expensive, and you can see it then.