Didanosine (ddI) that inhibits the reverse transcriptase of human immunodeficiency virus (HIV) causes steatosis and fulminant hepatitis in some patients with HIV. We studied hepatic histopathologic changes with particular attention to ddI-induced Mallory body formation. Three liver biopsies were performed on three patients with HIV who were treated with ddI; an autopsy was performed on a patient with HIV who was also treated with ddI. All hepatic specimens were studied with a routine liver immunohistochemical panel including antibodies to ubiquitin and cytokeratin (CAM 5.2). Morphologically, all hepatic specimens showed focal to diffuse steatosis with a predominance of macrovesicular fatty change. Fibrosis was minimal in three cases. No secondary bacterial and fungal infections were noted. Single or clusters of "empty cells" were present, and some contained Mallory bodies validated by ubiquitin stain. Empty cells are hepatocytes that fail to stain positive for cytokeratin. The Mallory bodies were different from the others because they were randomly distributed and occurred in noncirrhotic hepatic tissue. In the autopsy specimen, the Mallory bodies had a centrilobular location with central fibrosis (central sclerosing hyaline necrosis).