Isner is 5-3 in Davis Cup singles matches, including wins this year over No. 1-ranked Roger Federer and sixth-ranked Jo-Wilfried Tsonga as the U.S. team defeated Switzerland and France to get to the semifinals.
U.S. captain Jim Courier will have twin brother doubles specialists Bob and Mike Bryan for the third match in the best-of-five series. Bob Bryan is 20-2 and Mike Bryan is 21-2 in Davis Cup play.
Spain will be without No. 3-ranked Rafael Nadal, who has tendinitis in his left knee. But the defending Davis Cup champions will have world No. 5 David Ferrer, 12th-ranked Nicolas Almagro, Marcel Granollers and Marc Lopez.
As expected, Spain has chosen a red clay court for the series, to be decided Sept. 14-16 in Gijon, Spain. Ferrer is 14-0 in Davis Cup play on clay and Almagro is 7-1.
The winner of the Spain-United States semifinal advances to the 2012 Davis Cup title series Nov. 16-18 against either Argentina or the Czech Republic.