A 75 year-old woman presented with a one month history of diarrhea. She had 5 non-bloody, liquid stools per day, abdominal cramping and urgency. She denied fevers, vomiting, and recent antibiotic use. Her past history included chronic myelomonocytic leukemia (CMMoL), diagnosed 6 years ago and managed expectantly, as well as hypothyroidism, GERD, and non-specific arthralgias. On physical exam, the patient was well-appearing with a normal abdomen. Rectal exam revealed external hemorrhoids, a normal sphincter, and an empty vault. Laboratories noted a hemoglobin of 9.1 g/dl, platelets of 103K and WBC count of 24K. These were stable and consistent with her CMMoL. Stool analysis was negative for infection. Serologies included an elevated pANCA, normal ASCA and anti-OMPC, and negative celiac antibodies. Complete colonoscopy revealed friable mucosa, with multiple erosions from the anus to the cecum. Random biopsies showed diffuse chronic and active acute colitis without viral inclusions. A diagnosis of ulcerative colitis was made and treatment with mesalamine was unsuccessful. Prednisone resulted in partial relief of diarrhea, but was discontinued due to irritability and myopathy. Repeat colonoscopy at our center revealed pancolitis with rectal ulcerations and nodularity. Biopsies were consistent with leukemic infiltration of the colonic mucosa with an atypical mucosal infiltrate of monocytes and granulocytes; B and T cell immunohistochemical stains were positive for CD3, L26 and PAX5, and polyclonal plasma cells were mildly positive for CD68 and CD43. There was no evidence of acute blastic transformation. Therapy with hydroxyurea and rectal mesalamine resulted in a normal WBC count and relief of the diarrhea. After 3 years, the patient's diarrhea recurred in association with a rising peripheral WBC and acute disseminated encephalomyelitis. Rectal biopsies confirmed recurrent active leukemic colitis. This case demonstrates leukemic infiltration of the colon, presenting as chronic diarrhea. GI tract involvement occurs in 5–10% of all leukemias, although case series suggest an even lower incidence in CMMoL. This process can affect any part of the GI tract and may present in a variety of ways, ranging from asymptomatic to frank perforation. Heightened clinical suspicion for this entity must be maintained in patients with any form of leukemia who present with unexplained diarrhea. As our patient demonstrates, systemic therapy addresses both the underlying leukemia and its GI manifestations.