Defenders Winston Reid and Guy Demel are West Ham's main injury concerns.
Reid (back) and Demel (thigh) will have to prove their fitness ahead of the match, while the Hammers will also be without Ricardo Vaz Te who has had surgery on his dislocated shoulder.
Andy Carroll came through England duty unscathed and is expected to start up front, while Raphael Spiegel will back up Jussi Jaaskelainen in goal, with Stephen Henderson beginning his three-month loan with Ipswich.
Southampton will be missing record signing Gaston Ramirez for the trip to Upton Park and the foreseeable future.
The 21-year-old faces another four weeks out after problems related to a dead leg picked up before the international break and will be joined on the sidelines by Frazer Richardson (thigh).
Jack Cork, Danny Butterfield (both knee) and Tadanari Lee (elbow) are also out, but Nathaniel Clyne is set to return. Artur Boruc could be involved with Southampton for th e first time.
West Ham (from): Jaaskelainen, McCartney, Collins, Noble, Jarvis, Diame, Nolan, Carroll, O'Neil, Benayoun, Maiga, Cole, Spence, Diarra, Tomkins, Collison, Spiegel, Driver.
Southampton (from): K Davis, Gazzaniga, Boruc, Butterfield, Stephens, Clyne, Fox, Shaw, Yoshida, Hooiveld, Fonte, Seaborne, Ward-Prowse, Do Prado, Chaplow, De Ridder, Lallana, Schneiderlin, Puncheon, S Davis, Lambert, Rodriguez, Mayuka.
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