Potent virus-specific cytotoxic T lymphocyte (CTL) responses elicited by candidate AIDS vaccines have recently been shown to control viral replication and prevent clinical disease progression after pathogenic viral challenges in rhesus monkeys. Here we show that viral escape from CTL recognition can result in the eventual failure of this partial immune protection. Viral mutations that escape from CTL recognition have been previously described in humans infected with human immunodeficiency virus (HIV) and monkeys infected with simian immunodeficiency virus (SIV). In a cohort of rhesus monkeys that were vaccinated and subsequently infected with a pathogenic hybrid simian-human immunodeficiency virus (SHIV), the frequency of viral sequence mutations within CTL epitopes correlated with the level of viral replication. A single nucleotide mutation within an immunodominant Gag CTL epitope in an animal with undetectable plasma viral RNA resulted in viral escape from CTLs, a burst of viral replication, clinical disease progression, and death from AIDS-related complications. These data indicate that viral escape from CTL recognition may be a major limitation of the CTL-based AIDS vaccines that are likely to be administered to large human populations over the next several years.