Immunoglobulin isolated from sera of homosexual men infected with human immunodeficiency virus (HIV) inhibited the reverse transcriptase (RT) activity of HIV. The inhibitory activity was specifically directed against HIV RT, and not against other mammalian retrovirus RT, including human T-lymphotropic virus type I. The relative titer of anti-RT antibody was significantly higher in asymptomatic men than in patients with lymphadenopathy or acquired immune deficiency syndrome (AIDS)-related complex. There was no correlation between the relative titer of anti-RT antibody and the relative titers of antibodies to major virion structural protein as determined by the enzyme-linked immunosorbent assay (ELISA) technique. These data suggest that antibodies to HIV RT may be related to the clinical status and possibly to the different degree of HIV replication in HIV-infected homosexual men.