During antiretroviral therapy, CD4 lymphocyte count increases are modest in some patients despite virologic control. We explored whether polymorphisms in genes important for T cell expansion, survival, and apoptosis are associated with the magnitude of CD4 lymphocyte count recovery during antiretroviral therapy. We studied treatment-naive individuals who achieved sustained control of plasma viremia (<400 HIV-1 RNA copies/mL) for at least 48 weeks after initiation of antiretroviral therapy and compared genotypes among individuals who had an increase of either <200 or > or =200 CD4 cells/mm3 from baseline. A total of 137 single-nucleotide polymorphisms across 17 genes were characterized in 873 study participants. In multivariate analyses that controlled for clinical variables, polymorphisms in genes encoding tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), TNF- alpha , Bcl-2-interacting molecule (Bim), interleukin (IL)-15, and IL-15 receptor alpha chain (IL-15R alpha ) were associated with the magnitude of the increase in CD4 lymphocyte count, as were haplotypes in genes encoding interferon- alpha , IL-2, and IL-15R alpha (P < .05, for each). Multifactor dimensionality reduction identified a gene-gene interaction between IL-2/IL-15 receptor common beta chain and IL-2/IL-7/IL-15 receptor common gamma chain. Immune recovery during antiretroviral therapy is a complex phenotype that is influenced by multiple genetic variants. Future studies should validate these tentative associations and define underlying mechanisms.