There is a lack of information about the stability of these responses over time in subjects experiencing differences in HIV disease progression. The functional profile of Gag-specific and Nef-specific CD8+ T-cell responses based on the simultaneous production macrophage inflammatory protein (MIP)-1β, interleukin (IL)-2, and tumor necrosis factor (TNF)-α was longitudinally assessed using flow cytometry over 4 years in 8 elite controllers (EC), 8 viremic controllers, 10 antiretroviral-naive typical progressors, and 10 patients with virological suppression (VS) on antiretroviral therapy. CD8+ T-cell subsets with 2 functions tended to decline, whereas subsets with 1 function tended to increase over time in typical progressors. In viremic controller, Gag and Nef responses evolved differently. In EC, the functional profile of Gag-specific CD8+ T-cell responses evolved increasing polyfunctionality over time. Finally, Nef-specific responses in VS increased in the MIP+ TNF-IL2-CD8+ T-cell subset while Gag-specific responses did not change. The functional profile of HIV-specific CD8+ T-cell responses may evolve in different ways depending of the targeted HIV protein and the ability to control virus replication. In patients with uncontrolled HIV replication, the functionality of Gag-specific CD8+ T-cell responses tends to diminish over time, whereas in EC, there is an increase in polyfunctional subsets. Interestingly, VS do not seem to restore the polyfunctional profile of HIV-specific CD8+ T-cell responses.