BACKGROUND: Multiple host factors may influence CD4(+) T cell reconstitution in human immunodeficiency virus (HIV)-infected patients after suppressive antiretroviral therapy (ART). We hypothesized that residual immune activation and polymorphisms in the interleukin 7 (IL-7) receptor alpha (IL-7Ralpha) gene were important for immune recovery. METHODS: We examined HIV-infected patients receiving suppressive ART (n = 96) for their IL-7Ralpha haplotypes and measured levels of lipopolysaccharide (LPS), soluble CD14, and IL-7 in plasma samples collected before and after ART initiation. Levels of soluble IL-7Ralpha were measured in HIV-infected patients with IL-7Ralpha haplotype 2 (n = 11) and those without IL-7Ralpha haplotype 2 (n = 22). Multivariate analysis was used to identify variables associated with faster recovery to CD4(+) T cell counts of >500 and >200 cells/muL. RESULTS: Both LPS and soluble CD14 levels were significantly decreased with ART (P < .001, respectively) but remained elevated compared with uninfected controls. In a multivariate analysis, faster recovery to a CD4(+) T cell count of >500 cells/muL was significantly associated with higher baseline CD4(+) T cell count, younger age, lower pre-ART LPS level, higher pre-ART soluble CD14 level, lower pre-ART IL-7 level, and IL-7Ralpha haplotype 2 (hazard ratio, 1.50; 95% confidence interval, 1.03-2.19; P = .034). HIV-infected patients with haplotype 2 had significantly lower soluble IL-7Ralpha levels compared with those of patients without haplotype 2 (P < .001). CONCLUSION: Both the extent of immune depletion prior to ART and IL-7Ralpha haplotype 2 are important determinants of time to CD4(+) T cell recovery to counts of >500 cells/muL.