Because surgery in obese patients is associated with a high risk of infection, gastric bypass procedures offer an excellent opportunity to test the efficacy of prophylactic antibiotics. Accordingly, a double-blind prospective trial of prophylactic cefazolin was carried out in 53 consecutive patients who underwent gastric bypass surgery for morbid obesity. The patients were randomized to two treatment arms: (1) cefazolin intravenously, 1 gm 2 hours prior to surgery, at induction of anesthesia, and then 0.5 gm every 6 hours for 48 hours, or (2) an indistinguishable placebo of 5% dextrose at identical intervals. Serial cultures were taken at operation and in the postoperative period. Antibiotic levels of fat were measured by tissue extraction and B. subtilis assay. After surgery, patients were monitored for infection by clinicians unaware of their random assignment group. The study was terminated and the code broken when it was evident that wound infections were increased to a statistically significant difference in one arm of the study. The brief perioperative administration of cefazolin reduced the incidence of wound infection from 21% to 4% (P less than 0.05) and the incidence of urinary tract and pulmonary infections from 17% to 0% (P less than 0.05). Tissue levels of antibiotics confirmed adequate dosages in the test subjects. The advantages of prophylactic administration of cefazolin for gastric bypass procedures are clearly demonstrated in this study. This confirms other reports which have shown prophylactic antibiotics to be useful in a variety of procedures. These studies suggest the need to reconsider the traditional opposition to prophylactic antibiotics and to determine whether perioperative antibiotics should be used routinely in all major operations.