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Start with home airport and client city and see who has direct flights
Agree with D1- it really depends on where you are at.
I always recommend you go with whomever has a hub or the highest market share at your home airport. Otherwise, maintaining loyalty to an airline that doesn’t means you’re condemned to nearly always connecting and may require you to leave earlier Mondays and get home far later Thursdays, with greater risk of misconnecting along the way and losing even more time.
If your home airport has multiple hubs (really just LAX, ORD or if equidistant from airports in DC or NYC), then you may have to think harder.
What about JetBlue? Do they have hubs like the big airlines? I live in Boston so there are plenty of JetBlue flights here but not as much as the big 3 and I can't tell if they have flights around the country
BOS is an outlier. Its location in the far NE US makes it a poor domestic connecting hub as most connecting through it would have to backtrack to use it. But it has a strong economy and decent airline service, and more international service than its size would suggest it should.
JetBlue really only hubs at BOS and JFK but is a viable option for many in Boston. The only issue you’d have is if you need to go to smaller cities in, say, the Midwest that they don’t serve at all.