In an attempt to determine why high frequencies of circulating virus-specific CD8⁺ T cells are unable to control human immunodeficiency virus and simian immunodeficiency virus (SIV) replication, we assessed the functional nature of SIV-specific CD8⁺ lymphocytes. After vaccination and early after infection, nearly all tetramer-staining CD8⁺ cells produced gamma interferon in response to their specific stimulus. However, by 4 months postinfection with pathogenic SIVmac239, signs of functional impairment in the CD8⁺ T-cell compartment were detected which might prevent these T cells from efficiently controlling the infection during the chronic phase.