In a retrospective sequential study we determined the rate of infection occurring despite cephalothin or cephapirin chemoprophylaxis in orthopedic and cardiac surgery done from 1973 to 1977. The incidence of infection after prosthetic hip placement or open reduction of hip fracture was 3.4% and 1.0% in patients receiving cephalothin or cephapirin, respectively. The infection rate after prosthetic heart valve implantation was 3.5% in those receiving cephalothin and 1.6% in those receiving cephapirin. There was no significant difference in infection rate, duration of fever greater than or equal to 38.0 C, or length of postoperative hospitalization. The efficacy of selected antistaphylococcal antibiotics in preventing colonization of human fibrin clots by staphylococci was studied. Although cephapirin was effective at lower concentration, the activity of cephalothin and cephapirin was comparable. Cephalothin and cephapirin have equivalent chemoprophylactic activity by clinical and microbiological criteria, permitting cost to be used as a basis for choosing between these antibiotics.