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Background and Hypothesis: Activation of the NOD-like receptor protein (NLRP3) inflammasome has been postulated in mediating inflammatory responses to brain damage during ischemic reperfusion (I/R) injury. In this study, we therefore hypothesized that MCC950, a selective NLRP3-inflammasome inhibitor provides protection in a mouse model of ischemic stroke.Methods: Transient focal cerebral ischemia was induced by 60 min middle cerebral artery occlusion (MCAO) followed by 23 h reperfusion in mice. MCC950 (50 mg/kg) or saline was administered intraperitoneally at 1 h and 3 h post-occlusion. After 24 h of I/R, mice were tested for neurobehavioral outcome and were sacrificed for infarct size analysis and estimation of inflammasome and apoptotic markers.Results: MCC950-treated mice showed a substantial reduction (28%) in the infarct size (% contralateral hemisphere) and edema (29%) compared to saline controls. Further, administration of MCC950 after MCAO reduced the brain hemorrhage compared to saline treated mice. MCC950 treatment significantly (P<0.05) inhibited the expression of NLRP3-inflammsome components, and suppressed inflammatory and apoptotic damage (Table 1).Conclusion: Taken together, these data indicate that inhibition of NLRP3-inflammasome with MCC950 may have therapeutic potential in ischemic stroke model. Further investigations into the role and mechanisms of NLRP3 inhibition are needed to determine whether it can be an effective therapy for stroke patients.