Amoxicillin/clavulanic acid (amoxicillin 2 g/clavulanic acid 200 mg) has been administered in comparison to cefotaxime (2 g) for antimicrobial prophylaxis in 476 evaluable patients undergoing abdominal surgery at high risk of septic complications. Both antibiotics were administered as a single infusion. 205 evaluable patients (110 in amoxicillin/clavulanic acid group and 95 in cefotaxime group) underwent upper gastrointestinal surgery (including gastroduodenal and biliary surgery). The wound infection rate was 4.5% for amoxicillin/clavulanic acid and 7.4% for cefotaxime, with no significant differences. Intra-abdominal abscesses were observed in 3 patients in the amoxicillin/clavulanic acid group and in 1 patient in the cefotaxime group. 271 evaluable patients (135 in amoxicillin/clavulanic acid group and 136 in cefotaxime group) underwent lower gastrointestinal surgery (including colorectal surgery). The wound infection rate was 11% for amoxicillin/clavulanic acid and 13% for cefotaxime, with no significant differences. A purulent discharge was present in 3 patients in both groups. Intra-abdominal abscesses were observed in 3 patients in the amoxicillin/clavulanic acid group and in 4 patients in the cefotaxime group. No serious adverse events and no cases of diarrhea were observed. In conclusion, in our experience amoxicillin/clavulanic acid proved to be as effective as cefotaxime in protecting patients from surgical infections in abdominal surgery. Its use in surgical prophylaxis may help decrease the cost of treatment and reduce the risk of resistance to antibiotics and superinfections.