Opportunistic infection of the upper gastrointestinal tract by cytomegalovirus (CMV) or invasive fungal infection was studied in 219 consecutive kidney and kidney/pancreas transplant recipients with regard to incidence, presentation, and clinical outcome. Prompt upper endoscopy was done in all patients with these symptoms: dyspepsia, dysphagia, or bleeding. Multiple biopsies were obtained for fungal culture, CMV culture, CMV assay, and histologic examination for fungal invasion. Between April 1991 and July 1993, 57/219 (26%) transplant patients developed upper gastrointestinal symptoms. At endoscopy, gross mucosal abnormality was evident in 48/57 (84%). Opportunistic infection was found in 21/48 (44%); however, CMV infection was also detected in 2/9 (22%) who had a normal study. Overall, CMV was present in 15/57 (26%) and invasive fungal infection in 8/57 (14%). All 23 infections were successfully eradicated. Opportunistic infection occurred in 12/31 (39%) with dyspepsia, 9/14 (64%) with dysphagia, and 2/12 (17%) with bleeding. Graft loss occurred in 5/23 (22%) with opportunistic infection vs 23/196 (12%) other recipients. Upper gastrointestinal symptoms are indicative of serious opportunistic infection in a significant number of transplant recipients. As opportunistic infection may jeopardize allograft function, all patients with upper gastrointestinal tract symptoms require prompt endoscopy and biopsy to effect appropriate therapy. Random biopsy is also recommended in the face of a normal endoscopic examination.