OBJECTIVE Clostridium difficile gastrointestinal disease is an important nosocomial infection and is associated with recent antibiotic use. This study evaluated C. difficile-associated diarrhea (CDAD) over a 2-yr period. METHODS All 60 patients with C. difficile enterotoxin in their stools, and diarrhea, were retrospectively analyzed at a 615-bed teaching hospital. Institution antibiotic usage and discharge medical diagnoses were correlated with the study patients. RESULTS Thirty-eight study patients (53%) had major or extreme admitting symptoms. Only four (7%) had no co-morbid illness. The incidence of CDAD increased significantly (p < 0.05) after 4 wk of hospitalization. No demographic or temporal clustering was discovered. Leukocytosis (60%), leftward polymorphonuclear shift (47%), dehydration (30%), weight loss (23%), and oliguria (12%) were the major clinical findings. Among these subject 51 (85%) had been on ceftriaxone and/or ceftazidime in the preceding 6 wk; ceftriaxone/ceftazidime was highly significantly associated (p < 0.01) with more cases than expected by usage alone. No patient on ticarcillin/clavulanate developed CDAD, although it was the most commonly used antibiotic (p < 0.00001). Higher mortality was associated with older debilitated nursing home residents. CONCLUSIONS Third-generation cephalosporin use correlated with the development of CDAD; ticarcillin/clavulanate usage did not. Morbidity and mortality associated with CDAD is significant, is worse in debilitated older nursing home patients, and is more likely to occur in hospitalizations lasting longer than 4 wk.