Serum samples collected prospectively between 1982 and 1987 from a cohort of homosexual men were analyzed for HIV-1 neutralizing antibodies. Seven seroconverters who became infected between 1982 and 1984 and 12 seroprevalents who were already seropositive in 1982 remained free of AIDS. During the 6 year period, 1 seroconverter and 14 seroprevalents developed AIDS. Healthy seroconverters developed neutralizing antibodies slowly and reached moderate geometric mean titers (GMT) of 1:100 within 3 years of seroconversion. Healthy seroprevalents already had moderate titers in 1982, which increased markedly in 1985-1986 (GMT greater than 1:200) and subsequently returned to the previous level in 1987. Neutralizing antibody titers declined 3 years prior to diagnosis in men who developed AIDS and reached levels significantly lower than those of healthy counterparts 2 years before diagnosis. Analysis of neutralizing antibody activity to several HIV-1 isolates indicated that the lower titers of men who developed AIDS were not due to diminished group-specific reactivity. Thus, high neutralizing antibody titers correlated with better clinical outcome, and low or decreasing neutralizing antibody titer signaled poor prognosis. Although naturally developing neutralizing antibodies may ultimately be inadequate in controlling disease progression, measures able to boost the neutralizing antibody titer of individuals already infected with the virus or to elicit high-titer neutralizing antibodies in individuals at risk may yet prove beneficial in controlling viral spread in vivo or in preventing new infection, presumably in concert with cellular immunity.