In a study of 394 homosexual men recruited at the primary care level the prevalence of antibody to human T-lymphotropic retrovirus (HTLV-III) was higher among those with lymph node enlargement than among controls. The degree of abnormal immune function, as shown by abnormalities in immunoglobulin levels, immune complex activity and T-lymphocyte subsets, was correlated with the extent of lymphadenopathy. A similar pattern of immunologic abnormality was associated with seropositivity for HTLV-III antibody. However, HTLV-III seropositivity was the major determinant of immune function after adjustment for lymph node status. The results suggest that the immune dysfunction seen in patients with lymphadenopathy is due for the most part to the high prevalence of HTLV-III seropositivity in these populations. Lymphadenopathy, in many subjects, may in fact represent a physical sign of a stabilized compensated homeostatic host response. Factors responsible for severe immune decompensation associated with acquired immune deficiency syndrome (AIDS) may best be sought by prospective study of HTLV-III seropositive asymptomatic patients or those with stable persistent generalized lymphadenopathy and relatively normal immune function.