Mycophenolate mofetil (MMF) is a commonly used drug in the prevention of allograft rejection in patients with solid organ transplants. Although diffuse colitis has been described in MMF-related colitis, segmental colitis has not been reported. We report the case of a 64-year-old male on MMF therapy who presented for evaluation of afebrile diarrhea and abdominal pain. Flexible sigmoidoscopy revealed a segmental erythematous mucosa with ulceration in the sigmoid colon, descending colon, splenic flexure and proximal transverse colon. Biopsies of these areas showed dilated damaged crypts, eosinophilic epithelial changes and crypt abscesses with apoptotic bodies consistent with MMF-induced injury. MMF was discontinued, leading to a significant improvement of his symptoms.