BACKGROUND : Although indoor residual spraying (IRS) is an effective tool for malaria control, its use contributes to high insecticide exposure in sprayed communities and raises concerns about possible unintended health effects. OBJECTIVE : The Venda Health Examination of Mothers, Babies and their Environment (VHEMBE) is a birth cohort study initiated in 2012 to characterize prenatal exposure to IRS insecticides and exposures’ impacts on child health and development in rural South Africa. METHODS : In this report, we describe the VHEMBE cohort and dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene (DDE) serum concentrations measured in VHEMBE mothers when they presented for delivery. In addition, we applied a causal inference framework to estimate the potential reduction in population-level p,p′-DDT and p,p′-DDE serum concentrations under five hypothetical interventions. A total of 751 mothers were enrolled. RESULTS : Serum concentrations of p,p′ isomers of DDT and DDE were above the limit of detection (LOD) in ≥98% of the samples, whereas the o,p′ isomers were above the LOD in at least 80% of the samples. Median (interquartile range) p,p′-DDT and p,p′-DDE serum concentrations for VHEMBE cohort participants were 55.3 (19.0–259.3) and 242.2 (91.8–878.7) ng/g-lipid, respectively. Mothers reporting to have lived in a home sprayed with DDT for malaria control had ∼5–7 times higher p,p′-DDT and p,p′-DDE serum concentrations than those who never lived in a home sprayed with DDT. Of the five potential interventions tested, we found increasing access to water significantly reduced p,p′-DDT exposure and increasing the frequency of household wet mopping significantly reduced p,p′-DDT and p,p′-DDE exposure. CONCLUSION : Our findings suggest that several intervention approaches may reduce DDT/DDE exposure in pregnant women living in IRS communities.