Efficient use of prophylactic antibiotics in surgery demands their presence in adequate serum concentration at the time of maximal potential contamination. This cover should extend from the moment of incision until at least the time of removal of large tubes and intravenous connulas. Critical cardiac contamination may occur during the bypass procedure while the operation within the cardiac chambers is being done. This is a special danger in valve replacement with prostheses. The antibiotic regimen of the Cardiothoracic Unit was studied in 12 consecutive patients and was generally found to provide adequate antibiotic coverage throughout the surgical procedure, including the bypass procedure. In all patients, a reinforcing cephalothin dose on completion of bypass ensured adequate circulating cephalothin levels for the completion of surgery. Clearance of the cephalothin from the blood of patients was found to decrease markedly during cardiopulmonary bypass.