USA coach Mike Tolkin has named his line-up for the Pool B match against South Africa at the Olympic Stadium on Wednesday.
Tolkin has made 12 changes to the starting line-up that lost to Scotland, an unusually high figure for the Eagles.
Only twice have they made more changes between World Cup matches, having made 14 changes between their second and third, and between their third and fourth matches in 2011.
Only Phil Thiel, Samu Manoa and Blaine Scully have retained their places in the starting line-up from the Scotland match.
The match-day 23 includes seven players who have not played in Rugby World Cup 2015 so far. Five of them (Louis Stanfill, Matthew Trouville, Niku Kruger, Zach Test and Andrew Suniula) will start and two others (Joe Taufetee and Mate Moeakiola) are on the bench.
Trouville, Kruger and Test will make their World Cup debuts, while Taufetee could do the same by coming on as a replacement.
If he comes off the bench, Moeakiola (37) will become the third-oldest player to represent USA at the World Cup, behind fly-half Mark Williams (38 in 1999) and prop Fred Paoli (37 in 1991). He would also become the eighth USA player to feature in three World Cups.
Manoa will captain the Eagles for the first time in his test career.
USA: 15 Blaine Scully, 14 Brett Thompson, 13 Folau Niua, 12 Andrew Suniula, 11 Zach Test, 10 Shalom Suniula, 9 Niku Kruger, 8 Samu Manoa (c), 7 John Quill, 6 Danny Barrett, 5 Matthew Trouville, 4 Louis Stanfill, 3 Chris Baumann, 2 Phil Thiel, 1 Oli Kilifi
Replacements: 16 Joe Taufetee, 17 Zach Fenoglio, 18 Mate Moeakiola, 19 Titi Lamositele, 20 Cam Dolan, 21 Al McFarland, 22 Mike Petri, 23 Chris Wyles
Date: Wednesday, October 7
Venue: Olympic Stadium, London
Kick-off: 16:45 local (15:45 GMT)
Referee: Pascal Gauzere (France)
Assistant Referees: Nigel Owens (Wales), Mike Fraser (New Zealand)
TMO: George Ayoub (Australia)