Although T cell activation is associated with disease progression in untreated human immunodeficiency virus type 1 (HIV-1) infection, its significance in antiretroviral-treated patients is unknown. Activated (CD38⁺HLA-DR⁺) T cell counts were measured in 99 HIV-infected adults who had maintained a plasma HIV RNA level ⩽1000 copies/mL for a median of 21 months while receiving antiretroviral therapy. Patients with sustained viral suppression had lower levels of T cell activation than untreated patients but higher levels than HIV-uninfected control subjects. Persistent T cell activation was associated with decreased CD4⁺ T cell gains during therapy. For every 5% increase in the proportion of activated CD8⁺ T cells, 35 fewer CD4⁺ T cells/mm³ were gained. Increased T cell activation was associated with shorter duration of viral suppression, hepatitis C virus coinfection, frequent low-level viremia, and lower nadir CD4⁺ T cell counts. Interventions that directly target T cell activation or the determinants of activation may prove to be useful adjuvants to antiretroviral therapy