Prophylactic antibiotic regimens in trauma patients may be significantly altered by large fluid shifts and hyperdynamic physiologic responses. We prospectively studied prophylactic amikacin and clindamycin in 150 abdominal trauma patients requiring laparotomy, analyzing the effects of duration of coverage, dosing interval, and dose. No difference in infection rates was noted when 72-hour coverage was compared with 24-hour coverage (19% vs. 21%). Clindamycin dosed at 1,200 mg every 12 hours achieved acceptable serum concentrations; infection rates were not significantly higher than seen with 600 mg every 6 hours (21% vs. 12%,p> 0.05). High-dose (11 mg/kg) amikacin reduced infection rates in patients with high blood loss (p< 0.025), high Injury Severity Scores (p< 0.025), and no colon penetration (p< 0.005). These data suggest that high doses are more effective than long courses of antibiotics in reducing infections in trauma patients undergoing laparotomy.