The big-serving American claimed the ATP 250 title last year and is one of three top-20 players in the draw in 2014.
Frenchman Richard Gasquet and South African Kevin Anderson, beaten by Isner in the final in 2013, are also competing at the hard-court event.
The tournament marks Isner's first on hard courts since Miami, but he was solid on the grass at Wimbledon (third round) and Newport (quarter-finals).
Gasquet, the second seed, has struggled since reaching the final on the grass at Eastbourne.
He bowed out in the second round at Wimbledon before heading to the Claro Open Colombia, where he was favourite to win the title.
But Gasquet suffered a shock quarter-final loss to Victor Estrella Burgos on the hard courts in Bogota.
Anderson will be grateful for a return to hard courts, which suit his biggest weapons – his serve and forehand.
He enjoyed a decent clay-court season and was solid on grass, but his best results have been on hard.
All eight seeds are in the top 50, with Gael Monfils, Canadian Vasek Pospisil, Czech Radek Stepanek, Uzbek Denis Istomin and Lu Yen-hsun of Chinese Taipei also competing.
Entertaining Frenchman Monfils will also enjoy a return to hard courts as the US swing starts in preparations for the US Open.