Background Women at risk of preterm delivery receive magnesium sulfate (MgSO 4 ) in the pre-delivery phase to reduce their child's risk of neurodevelopmental complications associated with preterm birth. However, the mechanisms underpinning its placental vascular role remain uncertain. Methods The aim of this study was to examine MgSO 4 action on vascular tone in male and female human placental vessels from term and preterm deliveries. Vessels were obtained from placental biopsy following birth at term (37-41 weeks) or preterm gestation (gestation). The vessels were mounted on a pressure myograph, pre-constricted with synthetic endoperoxide prostaglandin PGH 2 (U46619) (0.1-100 μmol/l), and percentage of relaxation was calculated following incubation with bradykinin. Experiments were carried out in the presence of MgSO 4 (0.2 mmol/l), N Ψ -nitro-L-arginine methyl ester (L-NAME) (0.1 mmol/l), indomethacin (10 μmol/l), Ca 2+ -activated K + channel blocker TRAM-34 (1 μM) and apamin (3 μM) to assess mechanisms of vascular function. Vascular [calcium ions (Ca 2+ )] was analysed using a colorimetric calcium assay. Results Vasodilation in vessels from preterm males was significantly blunted in the presence of MgSO 4 when compared to preterm female and term male and female vessels. Overall, MgSO 4 was observed to differentially modulate placental vascular tone and vascular calcium concentrations in a sex-specific manner. Conclusions As MgSO 4 regulates human placental blood flow via specific pathways, foetal sex-specific MgSO 4 treatment regimes may be necessary. In an era of increasing awareness of individualised medicine, sex-specific effects may be of importance when developing strategies to optimise care in high-risk patients.