We have investigated the replicative capacity of 14 primary HIV-1 isolates in cultures of normal blood macrophages and PHA-stimulated peripheral blood mononuclear cells (PBMC). All viruses could infect normal macrophages as demonstrated by either reverse transcriptase (RT) activity, p24 antigen assay, or cocultivation with PBMC. One month after infection of macrophages virus could no longer be detected in the culture medium. The cells remained in this nonproductive state for another month. Virus could, however, be recovered by cocultivation with PHA-stimulated PBMC. Such macrophage-passaged virus induced pronounced cell killing with fragmentation and pyknosis and often replicated poorly in PBMC, in contrast to the original isolate. The results indicate that all primary HIV-1 isolates contain virus variants that can infect cells of the monocyte/macrophage lineage. Persistently infected, seemingly nonproducing cells, may serve as infectious reservoirs in the infected individual and spread infection to other susceptible cells over a long period of time. Moreover, the pronounced killing of PBMC by the macrophage-harbored virus may contribute to the deterioration of the immune system.