Abstract: Elevated soluble CD14 (sCD14) concentrations, a marker of monocyte activation, predicts adverse outcomes in human immunodeficiency virus (HIV)–infected adults. To examine the association of sCD14 concentrations with the risk of mother-to-child transmission (MTCT) of HIV, we nested a case-control study (49 pairs of infants and their HIV-infected mothers) within the Six-Week Extended-Dose Nevirapine trial. Median peripartum maternal log2 sCD14 concentration was higher among transmitters (defined as pairs in which maternally transmitted HIV infection occurred by 12 months of age) than nontransmitters (20.29 pg/mL vs 19.41 pg/mL; P = .005). There was an increased odds of MTCT for every log2 increase in maternal sCD14 concentration, after adjustment for maternal HIV load, CD4 count and cART exposure (adjusted odds ratio, 3.51; 95% confidence interval, 1.21–10.21). Maternal monocyte activation may adversely in- fluence the risk of MTCT of HIV.