A randomized, prospective study of the relative effectiveness of broad-spectrum versus specific antistaphylococal antibiotic prophylaxis in patients having open-heart surgery was performed between May, 1972, and June, 1973. All patients undergoing open-heart surgery was assigned randomly (by hospital number) to receive either methicillin or cephalothin beginning the night before operation. There were 132 patients in the cephalothin group and 129 in the methicillin group. There was no statistically significant differences in age or duration of hospitalization, cardiopulmonary bypass, urinary tract drainage, or postoperative fever. There was a significant difference in the ratio of male to total patients (cephalothin group, 0.67; methicillin group, 0.52; p less than 0.02) and duration of operation (cephalothin group, 4.27 hours; methicillin group, 3.87 hours; p less than 0.05). The methicillin group had a statistically significant higher rate of urinary tract infection (cephalothin group, 3 cases; emthicillin group, 22 cases, p less than 0.05), pneumonia (cephalothin group, no cases; methicillin group, 9 cases; p less than 0.01), and episodes of sepsis and prosthetic valve endocarditis (cephalothin group, no cases; methicillin group, 11 cases, p less than 0.001). The incidence of wound infections and positive blood cultures from blood obtained immediately after termination of cardiopulmonary bypass was not significantly different between the two groups. Cephalothin has replaced methicillin as the routine prophylaxis for open-heart surgery at our institution.