BACKGROUND Markers are needed for assessing response to antiretroviral therapy over time. The CD4+ lymphocyte count is one such surrogate, but it is relatively weak. OBJECTIVE To assess the association of changes in plasma human immunodeficiency virus (HIV) RNA level and CD4+ lymphocyte count with progression to the acquired immunodeficiency syndrome (AIDS). METHODS Analysis of data from a subset of patients in a multicenter, randomized, clinical trial. METHODS Six Veterans Affairs medical centers and one U.S. Army medical center. METHODS 270 symptomatic HIV-infected patients from the Veterans Affairs Cooperative Study on AIDS. METHODS Patients were randomly assigned to receive zidovudine or placebo initially; a cross-over protocol was established for patients receiving placebo who had disease progression. METHODS Reverse transcriptase polymerase chain reaction on cryopreserved plasma samples, previously obtained CD4+ lymphocyte counts, and clinical events. RESULTS For each decrease of 0.5 log10 copies/mL in plasma HIV RNA level, averaged over the 6 months after randomization, the relative risk (RR) for progression to AIDS was 0.67 (P < 0.001). In a subset of 70 treated patients with long-term follow-up, a return to baseline plasma HIV RNA levels within 6 months of randomization was associated with progression to AIDS (RR, 4.28; P = 0.004). Plasma HIV RNA levels or CD4+ lymphocyte counts over time were more strongly associated with progression to AIDS than were baseline levels or counts. CONCLUSIONS An adequate virologic response after initiation of antiretroviral therapy seems to require a decrease in plasma HIV RNA level of at least 0.5 log10 copies/mL that is sustained for at least 6 months. The independent relation between plasma HIV RNA level and CD4+ lymphocyte count over time and clinical outcome suggests that the measurement of plasma HIV RNA level, in addition to the CD4+ lymphocyte count, has a role in guiding the management of antiretroviral therapy.