Magnesium sulfate (MgSO) is utilized for fetal neuroprotection in preterm birth but its mechanism of action is still poorly understood. P2X7 receptor (P2X7R) is required for secretion of IL-1β, and can be blocked by divalent cations such as magnesium (Mg) and its own antagonist, Brilliant Blue G (BBG). We sought to determine whether during inflammation MgSO can block endothelial IL-1β secretion, using an in vitro model.Human umbilical vein endothelial cell (HUVEC) cultures were treated with varying doses of LPS, 2'(3)-Ο-(4-Benzoylbenzoyl) adenosine-5'-triphosphate (BzATP), BBG and MgSO for 3- or 24 h. We determined cell cytotoxicity, apoptosis, IL-1β mRNA expression, IL-1β production and secretion and P2X7R expression on HUVECs.We demonstrated that MgSO is efficacious in blocking IL-1β-mediated-inflammation in HUVECs, at both the initiation and propagation phases of inflammation. MgSO exerts these anti-inflammatory effects via downregulation of P2X7Rs on HUVECs.LPS-exposure increases IL-1β production and secretion in HUVECs, which is further intensified by P2X7R agonist, BzATP while MgSO inhibits IL-1β in both presence and absence of BzATP. This effect is similar to the results of P2X7R antagonist, BBG, suggesting that the anti-inflammatory effects of MgSO is through P2X7R.