Fetal growth restriction (FGR) defines a fetus which does not achieve its intrauterine growth potential. FGR is linked to placental dysfunction and hypoxia and is associated with a high risk of stillbirth, neonatal death and long-term complications; there are no treatments. Estrogen related receptor γ (ERRγ) is a nuclear receptor that is regulated by hypoxia in other systems; it is expressed in the placenta, thus we propose that it may be an important regulator of hypoxia-mediated placental dysfunction in FGR pregnancies. Placentas were collected from women delivering appropriate for gestational age (AGA; n=9) or FGR (n=9) babies, following informed consent. AGA placentas (n=8) were dissected and explants cultured for up to 4 days under normoxic (20%) or hypoxic (1%) conditions, or with cobalt chloride (CoCl2; 200 µM), a chemical inducer of hypoxia. hCG and LDH secretion were assessed by ELISA, as a proxy measure of placental cell proliferation and apoptosis. RT-PCR and western blotting assessed mRNA and protein levels of ERRγ in FGR, AGA and cultured explant tissues. Localization of ERRγ in placental tissue was studied by immunohistochemistry. ERRγ was predominantly localized to the maternal-facing syncytiotrophoblast layer of the placenta. ERRγ mRNA (n=9; P=0.02) and protein expression (n=10; P=0.01) were significantly decreased in FGR placentas. Both hypoxia and CoCl2 exposure dramatically decreased ERRγ mRNA expression (n=8; P=0.004 (hypoxia vs. control); P=0.02 (CoCl2 vs. control)) but not protein, significantly reduced expression of key signaling molecules downstream of ERRγ, including17β-hydroxysteroid dehydrogenase type 1 (HSD17B1), 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2), cytochrome P-450 (CYP19A1), and placenta specific-1 (PLAC1) (n=7; P value<0.05), and significantly reduced hCG secretion and increased LDH (n=6; P=0.03). These data demonstrate that ERRγ is a hypoxia-sensitive receptor in the placenta and suggests that altered ERRγ-mediated signalling may contribute to hypoxia-induced placental dysfunction in FGR.