Interleukin (IL)-2 production after stimulation with human immunodeficiency virus type 1 (HIV-1) envelope (Env) peptides, tetanus toxoid, and phytohemagglutinin was measured in peripheral blood mononuclear cells (PBMC) from 25 HIV-1-infected children with mild and 24 with severe clinical disease and from 15 uninfected children. Env-specific IL-2 production was detected in PBMC of 26.5% of HIV-1-infected children but in none of the uninfected. The absence of Env-specific responses at enrollment among infected children was associated with a 6-fold increased risk of mortality within a year, adjusting for clinical severity (P=.04). Among those with severe clinical disease, Env-stimulated IL-2 reactivity in PBMC was negatively correlated with HIV-1 RNA copy numbers in plasma at enrollment and was positively correlated with CD4 T cell percentages 1 year later. HIV-specific cellular immune responses may play a role in containing progression of HIV-1 infection in children, despite early deficits in cell-mediated immunity.