The ultrastructural alterations induced by human immunodeficiency virus (HIV) in human lymphoid cells have been evaluated. Electron microscopic examination of peripheral blood mononuclear cells (PBMC) from 14 male homosexuals with confirmed acquired immunodeficiency syndrome (AIDS) or AIDS-related complex revealed that tubuloreticular inclusions were present in 5-15% of the cell sections from each case. In 5 of 14 cases, cylindrical confronting lamellae were found in 1-2% of the cell sections. No retrovirus-like particles or surface membrane alterations were detected. Neither of these structural alterations was observed in control PBMC obtained from six HIV-seronegative, hepatitis B virus surface antigen (HBsAg)-positive carriers or in 11 healthy subjects. When primary cultures of CD4+-enriched lymphocytes were infected in vitro with HIV, tubuloreticular inclusions could be detected in 3-10% of the cell sections, but no cylindrical confronting lamellae-like structures were found. In contrast, neither of these alterations were seen in uninfected or HIV-infected H9-HT continuous cell lines. These in vivo and in vitro studies indicate that there is an association between the appearance of the tubuloreticular inclusions and cytopathic HIV infection, although no correlation between cytopathic changes and active viral replication was observed at the single cell level. Further studies will be required to establish the mechanism(s) of formation of the tubuloreticular inclusions and to determine their prognostic potential.