Clostridium difficile-associated diarrhea (CDAD) has a wide spectrum of disease severity. Studies have implicated immunosuppressants as a risk factor for severe disease. We hypothesized that solid organ transplant (SOT) patients with CDAD would be at greater risk for severe disease because of their profound immunosuppression. Adult SOT patients with CDAD seen at Duke University Medical Center between 1999 and 2003 were compared with a reference group of non-transplant patients with CDAD. The primary outcome was the development of complicated colitis defined as death, intensive care unit admission, or urgent colectomy within 30 days of diagnosis. A secondary outcome was relapse within 60 days. Eighty transplant and 86 non-transplant cases were reviewed. There was no significant difference in the development of complicated colitis (13.8% vs. 7.0%) or relapse rates (6.2% vs. 7.0%) between the 2 groups. In the entire sample, 18.5% of patients receiving corticosteroids unrelated to transplantation relapsed as compared with 4.5% not receiving corticosteroids (risk ratio 4.3, P=0.02). In conclusion, no significant difference was found in severity of CDAD between SOT patients and non-transplant patients. Exposure to corticosteroids was significantly associated with an increased risk of relapse and may warrant a longer treatment course.