Cytomegalovirus (CMV) infection of the gastrointestinal (GI) tract is common and is most often seen in patients with acquired immunodeficiency syndrome (AIDS), inflammatory bowel disease, or those receiving immunosuppressive therapy. CMV infection of the small bowel accounts for only 4.3% of all CMV infections of the GI tract. Isolated cases of small bowel perforation due to CMV have been reported in AIDS patients, and all but one patient has died. This article reports the first case of an ileal perforation due to transfusion-associated CMV infection in a critically-injured non-AIDS patient. Immediate surgical resection and antiviral therapy led to complete recovery. The development of abdominal pain, fever, watery diarrhea, and GI bleeding in a critically ill patient should prompt the clinician to consider the diagnosis of CMV enteritis. If standard stool pathogens and Clostridium difficile toxin studies are nondiagnostic, endoscopic evaluation and CMV serology should be obtained. If CMV infection is confirmed, ganciclovir therapy should be initiated without delay. If bowel perforation occurs. prompt surgical resection is indicated. A heightened level of suspicion for CMV infection in multiply injured trauma victims and other critically ill patients, with earlier recognition of potential small bowel involvement, can hopefully decrease the incidence of bowel perforation, which is usually a fatal event.