A 54-year-old man with no known medical history presented to the emergency department with a 10-day history of bloody diarrhea and a 3-month history of progressive, red skin lesions. Physical examination revealed cachexia; erythematous papules on the face, torso, and legs; edema of the legs and feet; purplish nodules in the posterior oropharynx; and a distended abdomen. Results of laboratory studies were notable for a positive test for human immunodeficiency virus, a CD4 count of 45 cells per cubic millimeter (reference range, 300 to 1400), and a viral load of 5.5 million copies per millimeter. Computed tomography of the whole body showed a pleural effusion on the right side, pericardial effusion, ascites, diffuse lymphadenopathy, and diffuse thickening of the bowel wall. An upper endoscopy and colonoscopy were performed. Erythematous, polypoid lesions were seen throughout the gastrointestinal tract, from the esophagus to the rectum (Panel A, duodenum; Panel B, sigmoid colon). Biopsy specimens from multiple lesions showed features consistent with Kaposi’s sarcoma. A diagnosis of Kaposi’s sarcoma with cutaneous and gastrointestinal involvement was made. During a prolonged hospital course, the patient also received a diagnosis of cytomegalovirus colitis, and coronavirus disease 2019–related pneumonia. The patient died on hospital day 32.