The effect of two prophylactic antibiotic regimens during cardiopulmonary bypass (CPB) was investigated in dogs. Airborne contamination was determined by spraying two different bacterial strains (Staphylococcus aureus and Serratia marcescens) into the air of the operating room. Dogs were operated on and underwent CPB with a bubble oxygenator. Pericardial suction, either conventional (blood-air) or selective (only blood), was used. Particularly in the first situation, an impaired humoral host defense is induced. In dogs given the regimen consisting of penicillin G (benzylpenicillin), gentamicin sulfate, and flucloxacillin, the number of contaminated sites for both bacteria was reduced (p less than .01) compared with those given cefuroxime. The effectiveness of the combined antibiotic regimen could be ascribed to increased serum bactericidal activity and polymorphonuclear leukocyte (PMN) killing capacity. Cefuroxime enhanced the PMN respiratory burst. As a result, two weeks postoperatively the rate of infection was small in both groups. We conclude that prior to CPB, antibiotics should be administered prophylactically to overcome a period of impaired humoral host defense during CPB.