Objective: Preeclampsia (PE) is a severe placental syndrome that likely results from placental oxidative stress and inflammation, and can lead to maternal hypertension and premature delivery. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activates several genes involved in antioxidant defense in the placentae, along with the ATP-binding cassette (ABC) transporters which regulate substrate flow between maternal and fetal circulation. Although several ABC transporters are down-regulated in PE, their exact mechanistic role is poorly understood. Methods& Results: In this study, we compared the levels of major ABC transporters and NRF2 in placentae of healthy full-term pregnant women and those with early and term onset PE. We found a significant decrease in the levels of Nrf2 and several ABC transporters in the placentae of early onset compared to term onset PE. In addition, women with term onset PE showed improved post-partum parameters (lower blood pressure, and greater placental and neonatal weights) compared to those with early onset PE. Mechanistically, Nrf2 knock-down/knockout downregulated the genes for ABC transporters and antioxidant enzymes, and upregulated proinflammatory factors, whereas Nrf2 upregulation had the opposite effects. Conclusions: Nrf2 protects the placenta against PE by activating the ABC transporter-mediated efflux, indicating a novel target in PE therapy.