United States are currently ranked 22 in Fifa's world rankings, 21 places below Spain.
Landon Donovan, who is expected to start against Spain, is the side's all-time top goalscorer with 45, one less than David Villa.
USA's win over Spain in 2009 saw them reach the final of the Confederations Cup, which they lost 3-2 to Brazil.
Bob Bradley's face Canada, Panama and Guadeloupe in the Group C of the Cold Cup, starting on Wednesday.
Spain’s 2-0 defeat to the United States in the 2009 Confederations Cup was Vicente del Bosque's first loss as national coach.
Del Bosque is the only international coach in history to begin his tenure with 10 consecutive wins.
This game is the first of three friendly games for Spain this summer, with a meeting with Venezuela to come on Wednesday before a prestigious clash against Italy in August.
David Villa is Spain's all-time goalscorer with 46, but also holds the record for most goals for Spain in a World Cup (5, with Emilio Butragueno), most international strikes in one season (13) and most consecutive goalscoring matches (six).
Only three members of Spain's squad play outside La Liga (Fernando Torres, David Villa and Pepe Reina - all in England).
Even though Carles Puyol and Xavi are absent, there are 11 players in total from Spain's big two teams, Barcelona and Real Madrid.
PROBABLE LINE-UPS
USA (4-4-2):
Howard; Cherundolo, Bocanegra, Onyewu, Bornstein; Buddle, Bradley, Jones, Donovan; Altidore, Dempsey
USA are missing the industry of Stuart Holden in midfield, with the Bolton midfielder still sidelined with a long-term injury.
Fellow midfielder Benny Feilhaber also misses out in a game in which coach Bob Bradley will look to give as many of his players as possible a run-out ahead of the Gold Cup.
Jozy Altidore and Clint Dempsey, the scorers when USA beat Spain in 2009, are set to start up front in a strong line-up.
Spain (4-4-2):
Casillas; Ramos, Pique, Albiol, Capdevila; Bruno, Xabi Alonso, Cazorla, Silva; Villa, Negredo
Coach Vicente del Bosque is set to include Sevilla striker Alvaro Negredo, with his new club team-mate Manu del Moral expected to make his debut late on in Foxborough.
Midfielder Bruno Soriano is also in line for a start, meaning there could be three Villarreal players in Spain's starting XI.
Spain are without both Xavi and Carles Puyol, with the latter recovering from a knee operation and likely to be sidelined for the entire summer.
Prediction
With United States warming up for next week's Gold Cup, the home side are likely to have more of a competitive edge than a Spain team who are probably already thinking about their summer holidays.
Both coaches are set to experiment, but Spain's superior technical ability is likely to be cancelled out by a determined US outfit. With that in mind, a draw seems the most likely outcome here.
Both coaches are set to experiment, but Spain's superior technical ability is likely to be cancelled out by a determined US outfit. With that in mind, a draw seems the most likely outcome here.
United States 1-1 Spain 
