Ischemic colitis has a myriad of causes. Primary amyloidosis is a rare cause of ischemic colitis with only a few case reports in the literature. We present an unusual case of ischemic colitis due to primary amyloidosis. A 69 year old woman, with history of activated protein C resistance and lower extremity deep vein thrombosis on chronic warfarin treatment, presented with 1-day history of bloody diarrhea and crampy abdominal pain. Three weeks before, she was hospitalized with similar symptoms at another medical facility and diagnosed with ischemic colitis by colonoscopy. After a week of bowel rest, total parental nutrition, and intravenous antibiotics, her symptoms had resolved. She remained asymptomatic until the night prior to her current admission. She was afebrile with a blood pressure of 108/66 mm Hg and a pulse of 109 beats per minute. Physical examination was significant for mild tenderness to palpation in the lower abdomen, without peritoneal signs. Laboratory evaluation revealed normal white blood cell count, hemoglobin of 11.9 g/dL, and an International Normalized Ratio of 5. Abdominal computed tomography showed nonspecific thickening of the colonic mucosa from the splenic flexure to the descending colon. Sigmoidoscopy revealed multiple large ulcers with areas of mucosal necrosis in the proximal sigmoid colon. Biopsies showed focal ulceration with necroinflammatory exudate. Mesenteric angiogram was unremarkable. On hospital day 7, she underwent a total colectomy with end ileostomy after ischemic changes were observed from mid transverse colon to rectosigmoid junction on intraoperative colonoscopy. Histology revealed extensive amyloidosis involving the omentum and entire colon with deposition in the muscularis mucosa, submucosa, and subserosa. Perivascular deposition of amyloid with luminal narrowing was also present. Serum electrophoresis and immunofixation revealed an IgG lambda monoclonal band, while a bone marrow biopsy showed 5–10% lambda restricted plasma cells. Our case illustrates that primary amyloidosis presenting as recurrent ischemic colitis may be missed despite thorough history, laboratory evaluation, radiographic studies and endoscopic biopsies.