Nerve growth factor (NGF) regulates B cell activation and differentiation and is an autocrine survival factor for memory B lymphocytes. We have reported recently that the number of memory B cells is reduced during HIV-1 infection. In this study we evaluated whether alteration in the NGF supply was involved in memory B cell loss in HIV-1-infected subjects. High rate of cell death in vitro was observed in memory B cells from HIV-1-infected individuals compared to uninfected donors (26·2 ± 2·5%versus 7·9 ± 1·4%, P < 0·001). The increased expression of Fas on memory B cells from infected subjects did not enhance the susceptibility of the cells to Fas-mediated apoptosis in vitro. The frequency of NGF detection in plasma from HIV-1-infected subjects was significantly lower than in healthy donors (33·6%versus 63·6%, P < 0·001). Also, the median plasma NGF in HIV-1-infected individuals was significantly lower than in uninfected controls (5 versus 14 pg/ml, respectively, P < 0·01). Interestingly, the plasma NGF level was correlated directly 1to the percentage of memory B cells (P < 0·05). HIV-1-infected subjects with a low number of peripheral memory B cells had a reduced incidence of plasmatic NGF (7·4%) compared to patients with a normal level of memory B cells (37%, P < 0·01). Moreover, the addition of recombinant NGF (1 µg/ml) to cultures of purified B cells reduced cell death of memory B cells from HIV-1-infected subjects from 24·04 ± 3·0% to 17·4 ± 1·3% (P < 0·01). HIV-1-infected individuals also carried higher levels of natural anti-NGF autoantibodies compared to uninfected subjects. In conclusion, we found that memory B cells from HIV-1-infected individuals are primed for cell death. Our study suggests an association between low frequency of plasma NGF detection and the increased cell death of memory B lymphocytes observed during HIV-1 infection. Low levels of NGF in plasma may be due to reduced supply or to NGF binding to natural anti-NGF autoantibodies.