Although several in vitro lines of evidence support the potential power of antibody-dependent cell-mediated cytotoxicity (ADCC) in controlling HIV infection, the role of ADCC in the pathogenesis of HIV infection in vivo remains uncertain. There are few studies to date that longitudinally determine the plasma ADCC activity in HIV-infected subjects. We sought to establish an SIV/macaque model to perform such a longitudinal study. In the rhesus macaque cohort studied here, three of five macaques (designated Group 1) maintained higher plasma ADCC activity for at least 1 year after inoculation with SIV/17E-Br. The ADCC activity of the two remaining macaques (Group 2) fell 12 weeks after inoculation. There were also differences in longitudinal measurements of anti-SIV envelope IgG titers and CD4 counts. Group 1 macaques maintained higher antienvelope IgG titers and higher CD4(+) T cell numbers as late as 60 weeks postinoculation, while Group 2 macaques had significantly lower titers at 1 year postinoculation and lower CD4(+) T cell counts by 30 weeks postinoculation. Our study shows a correlation between humoral response, ADCC activity, and disease progression (as measured by CD4(+) T cell counts). In these animals, ADCC activity is associated with delayed progression to AIDS. Further studies are underway to determine if ADCC is a protective immune response in SIV infection or if ADCC is a marker of intact cellular and humoral immune responses.