Cytomegalovirus (CMV) infection of the upper gastrointestinal tract is a major cause of morbidity in heart transplant recipients. Since April 1985, 201 patients underwent heart transplantation at our institution. Immunosuppressive therapy was with a triple drug regimen of cyclosporin A, prednisone, and azathioprine. Fifty-three of these patients had upper gastrointestinal symptoms, which primarily consisted of abdominal pain or nausea and vomiting despite prophylactic treatment with antacids, H2 blockers, or both. A total of 79 esophagogastroduodenoscopies were performed in this group; 15 patients required more than one esophagogastroduodenoscopy for recurrent symptoms. Of these 53 patients with persistent gastrointestinal symptoms, 16 (30.2%) had diffuse erythema or ulceration of the gastric mucosa (14), esophagus (1), and duodenum (1) with biopsy results that were positive for CMV on viral cultures (incidence, 8%). All patients with positive biopsy results were treated with intravenous ganciclovir at a dose of 10 mg.kg-1.day-1 in two divided doses for a period of 2 weeks. Recurrence developed in 6 patients (37.5%) and necessitated repeated therapy with ganciclovir. None of the 16 patients died as a result of gastrointestinal CMV infection. Patients who were seronegative for CMV and received a seropositive heart experienced earlier clinical manifestation of CMV infection. Infection of the upper gastrointestinal tract with CMV is a major cause of morbidity in cardiac transplant patients that may progress to a life-threatening complication if left untreated. Early diagnosis with esophagogastroduodenoscopy and biopsy for viral cultures is essential for documentation and proper management.