Background. In cross-sectional studies of chronically infected individuals, lymphoproliferative responses to human immunodeficiency virus (HIV) type 1 p24 Gag antigen have previously been associated with lower virus load. It was not known whether this association would be predictive of better clinical outcome in longitudinal studies. Methods. In blood samples from 608 HIV-seropositive individuals enrolled in a trial of glycoprotein 160 vaccine therapy over the course of 3-5 years, lymphoproliferative responses to HIV-1 antigens, tetanus toxoid (TT), and mitogens were measured and correlated with clinical outcome and other parameters of progression. Baseline lymphoproliferative responses to antigens and mitogens were used to categorize the cohort into responders or nonresponders. Results. Although response to recall antigens did not correlate with clinical indices of disease progression, positive baseline lymphoproliferative responses to p24 and TT were associated with lower plasma levels of HIV-1 RNA. Persistently positive lymphoproliferative responses to the antigens also inversely correlated with repeated measurements of virus load, although the significance was lost once the measurements were adjusted for virus load and CD4 + cell count at baseline, by use of generalized estimating equation analysis. Conclusions. These observations suggest that the effect of the association between lymphoproliferative response and virus load is established early during HIV-1 infection and does not increase over time and suggest that antigen-specific lymphoproliferative responses reflect the dynamic state of HIV-1 infection and are inversely associated with virus load.