Initiation of antiretroviral therapy during acute HIV-1 infection may prevent persistent immune activation. We analyzed longitudinal CD38+ HLA-DR+ CD8+ T-cell percentages in 31 acutely infected individuals who started early (median 43 days since infection) and successful antiretroviral therapy, and maintained viral suppression through 96 weeks. Pretherapy a median of 72.6% CD8+ T cells were CD38+ HLA-DR+, and although this decreased to 15.6% by 96 weeks, it remained substantially higher than seronegative controls (median 8.9%, P= 0.008). Shorter time to suppression predicted lower activation at 96 weeks. These results support the hypothesis that very early events in HIV-1 pathogenesis may result in prolonged immune dysfunction.