We studied 81 men (79 homosexuals and 2 drug abusers) with persistent lymphadenopathy to determine whether those at risk for AIDS-related opportunistic infections could be identified prospectively. (Sixty-nine of 76 [91 per cent] had antibodies to human T-cell lymphotropic virus Type III [HTLV-III], and 76 of 79 [96 per cent] had abnormal T4/T8 cell ratios.) During the follow-up period (mean +/- S.E.M., 12.9 +/- 0.5 months; range, 8 to 19), infections developed in none of 38 patients with lymphadenopathy alone and in only 1 of 15 (7 per cent) with antecedent herpes zoster infection; however, 13 of 28 (46 per cent) with lymphadenopathy accompanied by constitutional symptoms or oral candidiasis or both had opportunistic infections within the follow-up period. Among the results of various T-cell assays, only antigen-stimulated lymphocyte proliferation and gamma interferon generation, which were absent or barely measurable in those in whom AIDS ultimately developed, were of prognostic value. T cells from 15 patients, 11 of whom had constitutional symptoms or thrush, failed to generate antigen-induced gamma interferon; infections developed in 10 of these 15 (67 per cent) within a mean of 8.2 months. These results suggest that patients with AIDS-related complex who are at risk for opportunistic infections within a year can be identified by correlating clinical manifestations with antigen-stimulated T-cell responses--in particular, with the production of gamma interferon.