Pylephlebitis or infective suppurative thrombosis of the portal mesenteric venous system is an uncommon condition that can potentially be deadly if not recognized and treated early. Although most commonly associated with pancreatitis and diverticulitis, any intra-abdominal or pelvic infection occurring in the region drained by the portal venous system can cause this rare entity. We report a case of a 75-year-old woman who developed post polypectomy pylephlebitis following colonoscopy, a condition rarely reported in the literature.