The presence of both viral particles and antiviral mucosal proteins may represent critical determinants of perinatal human immunodeficiency virus type 1 (HIV-1) transmission. In 60 HIV-1-infected women, concentrations of the innate mucosal protein, secretory leukocyte protease inhibitor (SLPI), were lower in vaginal fluid samples from 17 women whose babies became infected than in samples from nontransmitting women (mean+/-SE, 57+/-11 vs. 557+/-177 ng/mL, respectively; P=.01). Rates of transmission among women with higher SLPI concentrations (>100 ng/mL) were lower than those among women with lower concentrations (<100 ng/mL; 8.7% vs. 40.5%, respectively; P=.01). Concentrations of other putative HIV-1-inhibitory innate immune factors were similar in both groups. Concentrations of vaginal HIV-1 tended to be higher in transmitting than in nontransmitting women (407 vs. 174 virions/mL; P=.09). Increased concentrations of selected innate mucosal immune factors, such as SLPI, seem to be associated with reduced rates of perinatal HIV-1 transmission and may contribute to natural antiretroviral defense.