We wanted to determine the value of single-versus multiple-antibiotic treatment in cases of penetrating abdominal trauma. Of 357 patients entered into a prospective, randomized, examiner-blinded study, 291 met all protocol criteria; 101 of these patients received cefoperazone alone, 95 were given ceftriaxone with metronidazole, and 95 were placed on metronidazole, gentamicin, and ampicillin. Aerobic and anaerobic bacterial cultures were obtained upon opening and closing the peritoneum. The three groups were found to be similar upon evaluation of key parameters, such as the median number of febrile days, morbidity, incisional wound infection, intra-abdominal abscess, septicemia, other infections, hospital stay, and death. Fifteen of 291 (5%) patients had infectious complications, and 12 (4.1%) developed noninfectious complications. There were six (2.1%) deaths, two in each antibiotic group. Noninfectious complications occurred more frequently in the triple-antibiotic group, which was statistically significant (P = 0.013). There were no therapeutic failures, and therefore, the routine usage of additional antibiotics to cover for enterococcus needs justification.