Establishing a CD8+ T cell-mediated immune correlate of protection in HIV disease is crucial to the development of vaccines designed to generate cell-mediated immunity. Historically, neither the quantity nor breadth of the HIV-specific CD8+ T-cell response has correlated conclusively with protection. Here, we assess the quality of the HIV-specific CD8+ T-cell response by measuring 5 CD8+ T-cell functions (degranulation, IFN-γ, MIP-1β, TNF-α, and IL-2) simultaneously in chronically HIV-infected individuals and elite nonprogressors. We find that the functional profile of HIV-specific CD8+ T cells in progressors is limited compared to that of nonprogressors, who consistently maintain highly functional CD8+ T cells. This limited functionality is independent of HLA type and T-cell memory phenotype, is HIV-specific rather than generalized, and is not effectively restored by therapeutic intervention. Whereas the total HIV-specific CD8+ T-cell frequency did not correlate with viral load, the frequency and proportion of the HIV-specific T-cell response with highest functionality inversely correlated with viral load in the progressors. Thus, rather than quantity or phenotype, the quality of the CD8+ T-cell functional response serves as an immune correlate of HIV disease progression and a potential qualifying factor for evaluation of HIV vaccine efficacy. © 2006 by The American Society of Hematology.