Isolated ulcers of the large intestine are not associated with an underlying colitis and may be an incidental finding on screening colonoscopy or present with abdominal pain, hematochezia, chronic gastrointestinal bleeding, and rarely, perforation. A common cause of isolated colonic ulcers is the use of nonsteroidal anti-inflammatory drugs (NSAIDs), with ulcers in the cecum and right colon. Isolated rectal ulcers are caused by ischemia, solitary rectal ulcer syndrome (SRUS), radiation, or fecal impaction. Stercoral ulceration and nonspecific ulcers of the colon are rare but can cause colonic perforation. Infectious causes include tuberculosis and amebiasis. Histology is important to rule out malignancy but is not helpful for diagnosis except in SRUS and certain infections. The approach to isolated colonic ulceration includes biopsy of the ulcer and surrounding tissue, cessation of any NSAIDs, management of constipation, and recognition of the patient with SRUS. Inflammatory bowel disease should be ruled out in appropriate patients.