Data from 1330 human immunodeficiency virus type 1 (HIV-1)-infected patients enrolled in seven antiretroviral treatment trials were analyzed to characterize the clinical benefit of treatment-mediated reductions in plasma HIV-1 RNA levels. The risk of a new AIDS-defining event or death was reduced proportionally to the magnitude of the reduction of the HIV-1 RNA level during the first 6 months of therapy. Pretherapy HIV-1 RNA levels were prognostic independently of on-therapy levels. In addition, the reduction in risk associated with any given reduction of the level of HIV-1 RNA did not vary by pretherapy level. Having either a reduction in HIV-1 RNA level or an increase in CD4+ lymphocyte count, or both, was associated with a delay in clinical disease progression. This indicates that patient prognosis should be assessed using both HIV-1 RNA and CD4+ lymphocyte responses to therapy.