What would the difference be other then $180. 4000cuft room.

I can't speak for the EP500, however, I currently have the EP350 in a 3500 cu ft room, that is open to some other rooms and one EP350 is very adequate, especially with my M60's. Once I get my downstairs HT done, the room will be more like 8000 cu ft. At that point I'll determine if I need another 350....

EP500 will go deeper into the very low notes and will probably have flatter frequency response.

2xEP350 will move more air, should do a better job of handling large rooms, guessing will play a bit louder than 1xEP500, and having two subs can often give you smoother bass and lessen the effect of room modes by having sound originate in two parts of the room.

Disclaimer -- I bought my sub before I realized Axiom even made subs, so I haven't heard either 350 or 500.