Persistent, generalized lymphadenopathy (PGL) is a recognized component of human immunodeficiency virus (HIV) infection. We conducted longitudinal studies of B and T cell function in seven homosexual men with HIV infection and PGL. All seven had abnormal antibody-mediated immunity as studied by sequential assessment of in vivo antibody responses after immunization with the T-dependent neoantigens bacteriophage phi X 174 and keyhole limpet hemocyanin (KLH), the T-independent tetradecavalent pneumococcal polysaccharide vaccine, and the recall antigens diphtheria and tetanus toxoid. Compared to HIV-negative heterosexual controls, PGL patients responded with lower antibody titers and, following immunization with phage, failed to develop immunologic memory and to switch from IgM- to IgG-isotype antibody. In vitro antigen-induced antibody production was markedly diminished; and some patients showed depressed mitogen responses. There was a correlation between the degree of compromised immunity and the clinical condition; those with the most severe symptoms showed the most extensive immune deficiency. Yet despite obvious immunologic impairment five of the seven men have remained clinically stable over a 3-year follow-up period.