To investigate the pathogenicity of a virus originating in a chimpanzee with AIDS (C499), two chimpanzees were inoculated with a plasma-derived isolate termed human immunodeficiency virus type 1 NC (HIV-1 NC ). A previously uninfected chimpanzee, C534, experienced rapid peripheral CD4 Ű T-cell loss to fewer than 26 cells/l by 14 weeks after infection. CD4Ű T-cell depletion was associated with high plasma HIV-1 loads but a low virus burden in the peripheral lymph node. The second chimpanzee, C459, infected 13 years previously with HIV-1 LAV , experienced a more protracted course of peripheral CD4 Ű T-cell loss after HIV-1 NC inoculation, resulting in fewer than 200 cells/l by 96 weeks postinoculation. The quantities of viral RNA in the plasma and peripheral lymph node from C459 were below the lower limits of detection prior to inoculation with HIV-1 NC but were significantly and persistently increased after superinfection, with HIV-1 NC representing the predominant viral genotype. These results show that viruses derived from C499 are more pathogenic for chimpanzees than any other HIV-1 isolates described to date.