CD8+ T-lymphocyte responses are crucial to the control of HIV-1; therefore, studying the CD8+ immune response in a naturally resistant population could provide valuable insights into an effective anti-HIV response in healthy uninfected individuals. Approximately 5-10% of the women in the Pumwani Commercial Sex Worker cohort in Nairobi, Kenya, have been highly exposed to HIV-1 yet remain HIV-IgG-seronegative and HIV-PCR negative (HIV(ES)). As IFN-gamma production correlates to cytotoxic function, the CD8+ T-lymphocyte IFN-gamma response to HIV p24 peptides was compared in HIV(ES) and HIV-infected (HIV+) individuals. Almost 40% of the HIV(ES) had a CD8+ IFN-gamma+ response that was five times lower in magnitude than that of the HIV+ group. The breadth of the response in HIV(ES) was very narrow and focused primarily on one peptide that is similar to the protective KK10 peptide. In the HIV+ group, low peripheral CD4+ counts negatively influenced the number of CD8+ cells producing IFN-gamma, which may undermine the ability to control HIV. Overall, many of the HIV(ES) women possess a HIV-1 p24-specific CD8+ IFN-gamma response, providing evidence to the specificity needed for an effective HIV vaccine.