Hemophiliac patients receiving factor VIII replacement therapy and homosexual subjects are at risk for the acquired immune deficiency syndrome. Immunologic abnormalities, especially depletion of helper T cell populations, have been noted in members of these groups and may parallel their clinical state. We have evaluated the peripheral blood immunologic status of a group of hemophiliac and homosexual subjects with and without persistent generalized lymphadenopathy (PGL). Although individuals with PGL had more abnormal T-lymphocyte parameters, including lower helper/suppressor ratios, than group members without lymphadenopathy, there were no significant differences noted within each respective risk group. However, differences between hemophiliac and homosexual patient groups were noted. T-lymphocyte subpopulations of hemophiliac patients with lymphadenopathy were significantly more abnormal than the corresponding homosexual groups. All groups had decreased lymphocyte proliferative responses to mitogen. Homosexual subjects with lymphadenopathy exhibited the most profoundly depressed lymphocyte mitogenic responses. We conclude that, although abnormalities of T-lymphocyte subpopulation and lymphocyte mitogenic responses exist within each risk group, homosexual subjects (both asymptomatic and with PGL) had lower mitogenic responses than would be expected for their T-lymphocyte helper/suppressor ratios as compared to either control subjects or hemophiliac patients. These findings suggest that additional factors are operative in the mononuclear cell populations of homosexual subjects that depress lymphocyte function. An analysis of these factors may help explain the higher incidence of AIDS in homosexual subjects as compared to hemophiliac patients.