Thein vitrosynthesis of HIV-1, p24-, reverse transcriptase (RT)- and gp120-specific immunoglobulin (lg) G by unstimulated peripheral blood mononuclear cells (PBMC) from 38 asymptomatic and 10 symptomatic HIV-1-seropositive individuals was analysed. In the majority of these individuals, spontaneous production of HIV-1− and gp120-specific lgG from PBMC cultures was demonstrated. In addition, in the majority of the PBMC cultures from individuals with high serum antibody titers to p24, spontaneous production of p24-specific lgG was shown. In contrast, no p24-specific lgG production was detected in PBMC cultures from seropositive individuals with low or no serum antibody titers to p24. A similar relationship between low or absent RT-specific serum antibody titers and the absence ofin vitroRT-specific lgG synthesis was not demonstrated. Furthermore, it was shown that the numbers of p24-specific B lymphocytes in circulation, as calculated by a spot enzyme-linked immunosorbent assay, were significantly lower in individuals with low serum antibody titers to p24. These results suggest that the decline in p24-specific serum antibodies observed during progression towards AIDS is not merely a reflection of the clearance via immune complexes, but may also be attributable, at least in part, to a reduction of p24-specific antibody-producing active B lymphocytes.