In a review of the results of toxin assays, twenty-five orthopaedic patients who had a Clostridium difficile infection and associated diarrhea were identified. The infection was due to the use of antibiotics in all but one patient. Seventeen patients had received the antibiotics prophylactically. The two most commonly implicated antibiotics were cefazolin and clindamycin, because those drugs had been commonly used for prophylaxis at the study institutions. However, other antibiotics were implicated. There was a positive correlation between the delay in diagnosis and the severity of the illness. A white blood-cell count of more than 20 x 10(9) per liter indicated severe disease in our survey. The possibility of Clostridium difficile infection should be considered in patients who have signs and symptoms that mimic those of intestinal obstruction. Patients who have an unexplained fever or high white blood-cell count and in whom diarrhea develops in the postoperative period should be treated immediately with metronidazole, and a specimen of stool should be obtained for an assay for Clostridium difficile toxin. If the diagnosis of Clostridium difficile infection is confirmed by the presence of toxin in the stool and the patient has persistent, severe diarrhea, oral administration of vancomycin should be added to the regimen. The duration of antibiotic prophylaxis should be minimized to decrease the risk of Clostridium difficile colitis.