A prospective, randomized double-blind study was undertaken to determine the safety and efficacy of single-dose versus multiple-dose piperacillin for primary cesarean operation prophylaxis. After informed consent was obtained, patients received either 4 gm of piperacillin intravenously as a single dose or three 2 gm doses of piperacillin intravenously 4 hours apart. One hundred sixteen patients were evaluated for response; postoperative infection at the operative site was prevented in 52/60 (86.6%) who received the single dose and 53/56 (94.6%) who received multiple doses. The types of postoperative infections that occurred were similar in those patients in each group who developed infection and all responded well to therapeutic drugs. No adverse reactions to piperacillin were noted. Demographic characteristics and risk factors for infection were comparable for the two groups. These data support the efficacy of single-dose prophylaxis with an appropriate antibiotic agent.