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Background: Nod-like receptor protein 3 (NLRP3) inflammasome is a multiprotein complex composed of NLRP3, caspase-1, and apoptosis-associated speck-like protein containing a caspase recruitment domain. Activation of NLRP3 inflammasome leads to interleukin-1β (IL-1β) upregulation and pyroptosis, a proinflammatory cell death characterized by increased cell size. Of note, calcium signaling is crucial for NLRP3 inflammasome activation. This study elucidated the effects of magnesium sulfate (MgSO 4 ), a potent calcium antagonist, on modulating NLRP3 inflammasome., Materials and Methods: THP-1 cells, the human monocytic leukemia cell line, were treated with lipopolysaccharide (LPS, 1 μg/ml) plus nigericin (5 μM) (the LPS + Nig group) and LPS plus nigericin plus MgSO 4 (20 mM) [the LPS + Nig + M(20)] to facilitate investigations. Levels of IL-1β, pyroptosis, and NLRP3 inflammasome induction as well as intracellular calcium were assayed., Results: IL-1β concentration of the LPS + Nig + M(20) group was significantly lower than the LPS + Nig group (P = 0.001). Cell size of the LPS + Nig + M(20) group was significantly smaller than the LPS + Nig group (P < 0.001). Level of pyroptotic cell death of the LPS + Nig + M(20) group was significantly lower than the LPS + Nig group (P = 0.004). NLRP3 mRNA and protein concentrations of the LPS + Nig + M(20) group were also significantly lower than the LPS + Nig group (P = 0.021 and P < 0.001). Similarly, apoptosis-associated speck-like protein containing a caspase recruitment domain speck formation ratio and caspase-1 concentration of the LPS + Nig + M(20) group were significantly lower than the LPS + Nig group (both P < 0.001). The change in intracellular calcium level of the LPS + Nig + M(20) group was significantly smaller than the LPS + Nig group (P = 0.001)., Conclusions: MgSO 4 inhibits NLRP3 inflammasome, IL-1β upregulation, and pyroptosis. The mechanism is consistent with decreased intracellular calcium levels., (Copyright © 2017 Elsevier Inc. All rights reserved.)