A prospective, randomized, open trial of a single intravenous dose of a new broad-spectrum and long-acting cephalosporin was compared with the effect of three doses of cefoxitin in a group of 70 women undergoing cesarean section who were at high risk for postoperative endomyometritis and wound infection. All patients either had ruptured membranes or were in active labor, or both, without clinically detectable chorioamnionitis at the time of prophylaxis. Forty-six women received a single 2 gm dose of cefotetan and 24 received 2 gm of cefoxitin every 4 hours to complete a three-dose regimen. Outcomes of infectious febrile morbidity due to endomyometritis (15% versus 8%), wound erythema (4% versus 12%), and other parameters were similar for cefotetan and cefoxitin, respectively. Both agents were well tolerated in this high-risk population. Within the limits of this study, single-dose cefotetan chemoprophylaxis appears to be comparable to multidose cefoxitin administration in reducing morbidity in operative site infections after cesarean section.