The in vitro lymphocyte proliferative response (LPR) and interferon (IFN)-gamma production in the presence of Toxoplasma antigen were evaluated in 97 human immunodeficiency virus (HIV)-1-infected patients with CD4 cell counts of <100 cells/microL (group 1), currently >300 cells/microL but previously <100 cells/microL (group 2), or always >300 cells/microL (group 3) and in 28 non-HIV-infected blood donors (group 4), all seropositive to Toxoplasma. In group 2, 81% of patients had a positive LPR, versus 20% in group 1 (P<10(-3)). IFN-gamma production was greater in group 2 than in group 1 (922 vs. 0 Deltapg/mL; P=10(-4)). Multivariate analysis found a significant association between a positive LPR to Toxoplasma antigen and a CD4 count >300 cells/microL (odds ratio [OR], 16.3; 95% confidence interval [CI], 5.3-50.2) and anti-Toxoplasma IgG titer >150 IU/mL (OR, 5; 95% CI, 1.6-15.2). Immune reconstitution under highly active antiretroviral therapy was associated with a restoration of immune responses against Toxoplasma.