Fetal growth restriction (FGR), which causes perinatal morbidity and mortality, is characterized by birth weight and body mass being below 10th percentile for gestational age. FGR babies are prone to develop cardiovascular diseases later in life. Inadequate placental transfer of nutrients from mother to fetus due to placental insufficiency is considered the underlying cause of FGR.We tested whether a defect in cystathionine-β-synthase (CBS)/H2S pathway promotes FGR.Placental CBS expressions were determined in women with FGR (n=10) and normal controls (n=15) by Western blotting and real-time qPCR. ELISA was used to determine angiogenic factors levels in plasma and first-trimester (8–12 weeks gestation) human placental explants. Time pregnant mice were treated with aminooxyacetic acid (AOA), a CBS inhibitor and mean arterial blood pressure (MBP), histological assessments of placenta and embryos were performed.Placental CBS expressions were significantly reduced in women with FGR. Inhibition of CBS activity by AOA reduced placental growth factor (PlGF) production from first-trimester human placental explants. Administration of AOA to pregnant mice had no effects on blood pressure, but caused fetal growth restriction and reduced PlGF production. Histological analysis revealed a reduction in the placental junction zone, within which trophoblast giant cells and glycogen cells were less prominent in CBS inhibitor-treated animals. Furthermore, H2S donor GYY4137 treatment restored fetal growth in pregnant mice exposed to high level of soluble vascular endothelial growth factor (VEGF) receptor-1 (sFlt-1).Placental CBS is required for normal placental development. Reduced CBS activity contributes to the pathogenesis of FGR but not preeclampsia. Therapeutic potentials of H2S therapy should be validated in additional mouse models and molecules developed for clinical studies.