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Human cytomegalovirus (HCMV) infection has been strongly associated to HIV-1 progression. We have investigated whether the magnitude of the overall peripheral blood mononuclear cell responses to HCMV stimulation correlated with HIV-1 progression.Blood samples were collected from 75 HIV-1-positive individuals on highly active antiretroviral therapy with CD4 count >500 cells per cubic millimeter and undetectable HIV RNA just before interrupting treatment. Specific interferon-γ (IFN-γ) HCMV cell responses were measured by an enzyme-linked immunospot (ELISPOT) assay. The results were analyzed by Kaplan-Meier survival curves, contingency tests, and the Cox proportional hazard models to evaluate the predictive value of peripheral blood responses to HCMV and the length of time that patients were off treatment.Patients were stratified into those with weak (<500 spot-forming units) or strong (>500 spot-forming units) IFN-γ responses to HCMV. During the 3-year follow-up, 51% of patients with strong responses remained untreated compared with 14% of patients with weak HCMV responses (P = 0.0015). Length of time without therapy was also longer in patients with stronger responses (hazard ratio = 2.08; P = 0.001). HCMV responses were still predictive of restarting therapy after adjusting for the CD4 nadir counts.Specific IFN-γ responses to HCMV may be employed as a predictive useful marker for the evolution of HIV-1 infection.