Increased trophoblast TNFα production is an important component of placental dysfunction in preeclampsia. However, the mechanism of increased TNFα production in the preeclamptic placenta is largely unknown. ADAM17 is a metallopeptidase that functions as a TNFα converting enzyme. In this study, we examined ADAM17 expression in placentas from normal and preeclamptic pregnancies and found increased ADAM17 expression in preeclamptic placentas compared to those from normal placentas, p < 0.05. Since hypoxia/oxidative stress is an underlying pathophysiology in the preeclamptic placenta, we further determined if hypoxia/oxidative stress could modulate ADAM17 expression and subsequently induce TNFα production in placental trophoblasts. Trophoblasts were isolated from normal term placentas and treated with cobalt (II) chloride (CoCl(2)), a hypoxia mimetic agent, at different concentrations. Our results showed that CoCl(2) induced a dose-dependent increase in TNFα production that is associated with enhanced ADAM17 expression. Trophoblast expressions of HO-1 (a sensor of cellular oxidative stress) and caspase-3 (an indicator of apoptosis) in response to CoCl(2) stimulation were also examined. We further found that metallopeptidase inhibitor GM6001 and ADAM17 siRNA could block CoCl(2) induced TNFα production, demonstrating the role of ADAM17 in TNFα production in placental trophoblasts. These results suggest that oxidative stress-induced increased ADAM17 expression could contribute to the increased TNFα production in preeclamptic placentas.