Cytomegalovirus (CMV) infection of the gastrointestinal tract is a common cause of morbidity and mortality in the acquired immunodeficiency syndrome. The proper recognition of CMV-infected cells in gastrointestinal mucosal biopsies is critical so that effective therapy is not delayed, preventing further viral dissemination. Although the pathology criteria for classic CMV inclusions have been well described, the occurrence of morphologically atypical inclusions has been reported but the inclusions are not well characterized. This study prospectively examined the relative frequency of classic and atypical CMV inclusions in gastrointestinal mucosal biopsy specimens from 13 human immunodeficiency virus-positive symptomatic patients. The results demonstrated that classic inclusions were rarely found, including four esophageal, one gastric, and one colonic biopsy specimens in which none were seen. However, atypical CMV inclusions were identified from all biopsy specimens examined; these inclusions were much more numerous than classic inclusions and could be categorized into three morphologic types. The atypical inclusions were difficult to precisely identify as CMV-infected cells, but in situ DNA hybridization for CMV was valuable in establishing their viral origin, thus permitting the correct etiologic diagnosis. © 1992.