Cephalothin, a common used agent for antimicrobial prophylaxis, was compared with cefamandole, a second generation semi-synthetic cephalosporin having a somewhat broader antimicrobial spectrum, in a randomized, double-blind clinical trial of 201 patients undergoing elective open heart surgery. Cephalothin was administered to 101 patients and 100 received cefamandole. The protocol was not followed in 23 patients, 11 of whom received cephalothin and 12 cefamandole. Of 90 patients who could be evaluated for efficacy of cephalothin, two developed superficial wound infections and one developed an asymptomatic urinary tract infection. Five of 88 patients who received cefamandole developed infections; urinary tract infections in two, mediastinitis in one, a superficial wound infection in one, and pneumonia in one after prolonged endotracheal ventilation. Both were well tolerated with no adverse reactions attributed to either antibiotic. Cephalothin and cefamandole appear to provide similar efficacy and patient tolerance in open heart surgery; however, the drug regimen for cefamandole cost $83, whereas it was $58 for cephalothin.