Diarrhea is common in transplant recipients. While the majority of cases are mild and transient, some are severe and prolonged, which can threaten graft survival through dehydration. While it is known that some immunosuppressive agents can elicit diarrhea, there does not appear to be any consensus on the role that other nonimmunosuppressive causes can play in transplant patients. The aim of the present open, nonrandomized, multicenter study was to identify nonimmunosuppressive factors involved in severe diarrhea in renal transplant patients. Patients (n = 108) with severe diarrhea (>/=3 stools/day for >/=7 days) were enrolled from 16 Belgian transplant centers. Patients were diagnosed according to an agreed flowchart that consisted of identification of possible infections, followed by changes in empirical and immunosuppressive treatment. Approximately 50% of patients experienced resolution of severe diarrhea following treatment for infections, dietary problems or diarrhea-causing concomitant medications. In conclusion, a large proportion of the severe diarrhea observed in renal transplant recipients is not associated with immunosuppressive therapy and can be treated through anti-infectives, changes to concomitant medication and other empirical treatments. Correct diagnosis of the cause of severe diarrhea in such patients should help to protect graft survival in transplant recipients.