BACKGROUND Morbidity and mortality are higher among human immunodeficiency virus (HIV) exposed but uninfected (HEU) infants than unexposed infants, particularly if the mother had a low CD4 count. We investigated the possible association between maternal immune depression during pregnancy and the risk of infection in HEU infants in the national French Perinatal Cohort (EPF). METHODS All neonates, born alive, to HIV-1-infected women enrolled in the EPF between 2002 and 2010 were included. The primary outcome was the first serious (hospitalization or death) infection during the first year of life. The main exposure variable was maternal CD4 cell count near delivery. The Kaplan-Meier method and multivariate Cox models were applied, with the different types of infections managed as competing events. RESULTS Among 7638 HEU neonates, 699 had at least 1 serious infection (of which 159 were bacterial) with a Kaplan-Meier probability of 9.3% (95% confidence interval, 8.7-10.0) at 1 year. The risk of serious bacterial infection during the first year of life significantly increased with lower maternal CD4 cell count, before and after adjustment for maternal CD4 cell count