This study addressed the role of T-cell immune activation in determining HIV-1 plasma viral load and CD4+ T-cell blood levels during HIV-1 infection. A decrease of blood CD4 levels and CD4/CD8 ratios and an increase of CD8 levels in both treated (n= 35) and untreated (n= 19) HIV-positive individuals were more strongly correlated to immune activation (log percentage of HLA-DR+ CD3+ cells; R=-0.78, R=-0.77, and R= 0.58, respectively; p<. 0001) than to CD4 T-cell proliferation (log percentage of Ki-67+ CD4+ cells; R=-0.57 [p<. 0001], R=-0.48 [p<. 001], and R= 0.37 [p<. 01], respectively) or to viral load (R=-0.36 [p<. 01], R=-0.23 [p=. 09], R= 0.13 [p=. 35], respectively). Because almost half of the Ki-67+ CD4+ cells were also positive for CTLA-4 (a marker for activated nonproliferating cells), the correlation of CD4 levels to Ki-67 expression is only partially related to cell proliferation and more likely represents mainly immune activation of the cells without proliferation. Taken together, these results suggest that immune activation is the major determinant of CD4 decline and should therefore be considered central for the monitoring of HIV infection and its outcome after antiviral treatment.