One hundred fifty-six patients with presumed or documented abdominal infections were treated with amikacin/metronidazole/placebo (Group 1, 56 patients), amikacin/clindamycin/placebo (Group 2, 57 patients), or amikacin/clindamycin/ampicillin (Group 3, 43 patients) to determine both the therapeutic efficacy of the various regimens and the type of complications due to Clostridium difficile. C. difficile diarrhea occurred in 15 of 156 patients (9.6%), and C. difficile colonization occurred in 14 of 156 patients (9%) during treatment and 30 days of follow-up. The number of C. difficile diarrhea cases in Group 1 (3 of 56) was significantly lower than in Group 2 (9 of 57, p less than 0.05), but not in Group 3 (3 of 43). Exclusion of all patients who received other antibiotics in the 30-day poststudy period revealed no C. difficile diarrhea or colonization in Group 1 (0 of 13) and an acquisition rate of 31% (14 of 45) with the regimens containing clindamycin (p less than 0.02). Successful treatment outcomes (106 evaluable patients) were not statistically different among the three groups (Group 1, 64%; Group 2, 76%; and Group 3, 88%), but these data were difficult to interpret because, by chance, significantly more patients in Group 1 had bacteremia at entry (p less than 0.01), and patients in Group 3 had significantly more biliary tract infections (p less than 0.02) and significantly more favorable acute physiology scores (p less than 0.05). Use of metronidazole can reduce complications related to C. difficile, particularly if additional antimicrobials other than aminoglycosides are avoided.