Mycophenolate mofetil, an immunosuppressive agent, is frequently used following bone marrow and solid organ transplantation. Diarrhea is a commonly seen side effect of mycophenolate mofetil, which may necessitate colonic biopsy in some patients. The histologic changes found in this setting have been reported to mimic self-limited colitis, graft-vs-host disease or inflammatory bowel disease in isolated case reports, and could pose diagnostic and management difficulties. The goal of this study is to define the spectrum of histologic changes in colonic biopsies associated with mycophenolate mofetil usage. All solid organ transplant patients who received mycophenolate mofetil and underwent colonic biopsy for gastrointestinal symptoms from 1999 to 2007 were included in the study. Patients who did not receive mycophenolate mofetil were used as controls. Various histologic features including architectural distortion, apoptosis, inflammatory infiltrate, Paneth cell metaplasia and mucin depletion were subjectively evaluated and scored (scale: 0-3) by two independent reviewers in a blinded fashion. Forty solid organ transplant patients underwent colonic biopsy for gastrointestinal symptoms during the study period. Biopsies from 69% of patients on mycophenolate mofetil showed histologic changes. Apoptosis (41%) and architectural distortion (66%) were seen more frequently in patients receiving mycophenolate mofetil as compared to the control group (13%). The histologic changes in patients receiving mycophenolate mofetil were categorized as normal/near normal (31%), inflammatory bowel disease-like (28%), graft-vs-host disease-like (19%), ischemia-like (3%) and self-limited colitis-like (16%) changes. Of the controls, only one patient showed a graft-vs-host disease-like histologic pattern. In conclusion, histologic changes are frequently associated with mycophenolate mofetil use and can resemble self-limited colitis, graft-vs-host disease and inflammatory bowel disease leading to diagnostic difficulties. Increased awareness of the histologic spectrum of mycophenolate mofetil-induced changes is required by the pathologist to avoid diagnostic errors.