As the prevalence of human immunodeficiency virus (HIV) infection continues to rise the clinician is encountered with a diagnostic challenge. Nonsurgical diseases such as acute colitis or enteritis can appear similar to such true surgical emergencies as abscess, perforation, or mesenteric ischemia. We report a case of fulminant hepatic failure associated with didanosine and masquerading as a surgical abdomen and compare the clinical, biologic, histologic, and ultrastructural findings with reports described previously. This entity should be kept in mind when evaluating the acute abdomen in the HIV-positive patient.