Human immunodeficiency virus type 1 (HIV-1)-specific cellular immune responses are elicited in a proportion of infants born to HIV-1-infected mothers and are associated with protection against vertical transmission. To investigate correlates of these HIV-1-specific responses, we examined levels of the immune activation markers neopterin, beta(2)-microglobulin (beta(2)-m), and soluble l-selectin (sl-selectin); the immunomodulatory and hematopoietic factors interleukin-7 (IL-7), stromal-cell-derived factor 1 alpha (CXCL12), and granulocyte-macrophage colony-stimulating factor (GM-CSF); and the immunoregulatory cytokine IL-10 among a group of newborns born to HIV-1-positive mothers who did not receive any antiretroviral drugs for prevention of perinatal HIV-1 transmission. Cellular immune responses to HIV-1 envelope (Env) peptides were also measured. We aimed to determine whether newborns who elicit HIV-1-specific cellular immune responses (Env(+)) and those who lack these responses (Env(-)) exhibit unique immune features. Our data confirmed that no Env(+) infants acquired HIV-1 infection. Among exposed, uninfected infants, Env(+) infants had reduced immune activation (as measured by beta(2)-m and sl-selectin levels in cord blood plasma) compared to Env(-) infants as well as reduced GM-CSF levels in cord blood plasma. There was also a reduced ability of cord blood mononuclear cells to be induced to produce GM-CSF among Env(+) infants. Maternal viral load was lower in Env(+) infants, suggesting that exposure to low levels of antigen may be responsible for priming the protective responses. These findings suggest that infants who are able to develop apparently protective HIV-1-specific cellular immune responses have immunological features and viral exposure histories that distinguish them from their nonresponder counterparts, providing new insights into the development of HIV-1 protective immunity.