We undertook a prospective randomized evaluation of cefamandole nafate, cefuroxime sodium, and cefazolin sodium as prophylaxis in open-heart operations. A total of 903 patients having an elective procedure were enrolled in the study, and 620 of them were eventually considered evaluable. There were no significant differences between the three study groups. The overall rate of infection and the rate of infection according to demographic variables was not significantly different between the three antibiotics. Serious complications and deaths were also similar between the three agents. The presence of multiple severe underlying conditions was a risk factor for infection, independent of the antibiotic used. We conclude that there are no differences in the efficacies of the three agents in preventing postoperative infections in patients having open-heart operation. Cefuroxime, principally because of its every-12-hour dose, is far less expensive than cefamandole or cefazolin.