The addition of 5-10% of fresh normal human serum (NHS) from normal individuals into a culture of primarily HIV-1-infected CD4+ leukemic T-cell lines CEM and MT4 was found to rescue the infected cells from cytopathic death, enabling the cells to achieve growth within 10 days. The HIV-1-infected cells cultured in ordinary medium with fetal calf serum (FCS) all died within 10 days. The effect of NHS was ascribed to human complement component factor B and one or more factor B-dependent heat-labile co-factors. The cells which survived in the presence of NHS rapidly lost surface expression of CD4 and became completely resistant to rechallenge by HIV-1. Viral genomes were dramatically reduced in surviving cells within 30 days, and one cell-line CEM completely expelled them during this period. The results suggest that factor B has protective and potential therapeutic significance in HIV-1 infection.