BACKGROUND Diarrhea is the most frequently reported adverse event in mycophenolate mofetil (MMF)-treated transplant patients. The aim of this study was to explore the gastrointestinal tract in MMF-treated renal transplant recipients with persistent afebrile diarrhea to characterize its nature and etiology. METHODS Renal transplant recipients with persistent afebrile diarrhea (daily fecal output >200 g) were prospectively investigated for infections, morphologic, and functional (gastrointestinal motility and intestinal absorptive capacity) integrity of the gastrointestinal tract; 26 patients met the inclusion criteria. RESULTS All but one patient had an erosive enterocolitis. Seventy percent of the patients had malabsorption of nutrients, contributing to the diarrhea. In +/-60%, an infectious origin was demonstrated and successfully treated with antimicrobial agents without changes in immunosuppressive regimen. In +/-40%, no infection occurred, but a Crohn's disease-like pattern of inflammation was noted. These patients also had a less pronounced bile-acid malabsorption but a significant faster colonic transit time, correlating with the trough level of mycophenolic acid (MPA). Cessation of MMF, however, was associated with allograft rejection in one third of these patients. CONCLUSIONS Persistent afebrile diarrhea in renal transplant recipients is characterized by erosive enterocolitis, which is of infectious origin in +/-60%. In +/-40%, a Crohn's disease-like (entero-)colitis was present. Because reduction or cessation of MMF was the only effective therapy, MPA or one of its metabolites may be suggested as a possible cause. However, reduction or cessation of MMF was associated with an increased risk for rejection.