Mesenteric vein thrombosis is an uncommon condition. Diagnosis is often difficult because of the nonspecific clinical presentation and findings on routine laboratory and radiological evaluation. Endoscopy is usually unrevealing. An underlying hypercoagulable state is often present, but protein S deficiency has rarely been implicated. We describe a case in which chronic inferior mesenteric vein thrombosis, with remarkable endoscopic findings, occurred as the initial presentation of type I protein S deficiency.