Bisphenol A (BPA) exposure during pregnancy is associated with low fetal weight, particularly in male fetuses. Expression of estrogen-related receptor gamma (ESRRG), a receptor for BPA in human placenta, is reduced in fetal growth restriction. This study sought to explore whether ESRRG signaling mediates BPA-induced placental dysfunction, and determine whether changes in the ESRRG signaling pathway are sex-specific. Placental villous explants from 18 normal term pregnancies were cultured with a range of BPA concentrations (1nM-1μM). Baseline BPA concentrations in the placental tissue used for explant culture ranged from 0.04nM-5.1nM (average 2.3nM ±1.9nM; n=6). Expression of ESRRG signalling pathway constituents and cell turnover were quantified. BPA (1μM) increased ESRRG mRNA expression after 24 hours in both sexes. ESRRG mRNA and protein expression were increased in female placentas treated with 1μM BPA for 24 hours, but were decreased in male placentas treated with 1nM or 1μM for 48 hours. Levels of HSD17B1 and PLAC1, genes downstream of ESRRG, were also affected. HSD17B1 mRNA expression was increased in female placentas by 1μM BPA; however, 1nM BPA reduced HSD17B1 and PLAC1 expression in male placentas at 48 hours. BPA treatment did not affect rates of proliferation, apoptosis or syncytiotrophoblast differentiation in cultured villous explants. This study has demonstrated that BPA affects the ESRRG signalling pathway in a sex-specific manner in human placentas and a possible biological mechanism to explain the differential effects of BPA exposure on male and female fetuses observed in epidemiological studies.