A penicillin-sensitive strain of Staphylococcus aureus was used to evaluate the efficacy of six antibiotic combinations in the therapy of an experimental infection in mice. One hour after intraperitoneal infection, animals were treated with penicillin G, erythromycin, clindamycin, gentamcicin, or tobramycin singly or in various combinations of two of these drugs. Penicillin in combination with tobramycin, gentamicin, or ertyromycin significantly reduced mortality was compared with therapy with a single drug. Survival of animals treated with the combinations of penicillin and clindamycin, clindamycin and gentamicin, and erythromycin and gentamicin was not different from that seen with single-drug therapy. Pencillin plus either gentamicin or erythromycin significantly reduced the number of culturable organisms from livers and spleens of infected animals when compared with penicillin, gentamicin, or erythromycin alone. In vitro studies correlaed with some aspects of in vivo results but conflicted with others. Thus the combination of penicillin with either an aminoglycoside antibotic or erythromycin is more effective than a single drug in the therapy of infection caused by the Smith strain of S. aureus.