Objective: Reperfusion following a period of ischemia is associated with the formation of reactive oxygen species (ROS) and the Ca²⁺ overload resulting in the opening of a non specific pore in the inner membrane of the mitochondria, called mitochondrial Permeability transition pore (PTP), leading to cell damage. Even though endogenous antioxidants are activated due to the oxidative stress following ischemia, their levels are not enough in preventing the reperfusion injury. Hence there is always a need for the exogenous supplement of the antioxidants especially following the acute ischemia. Here we have demonstrated the effects of the antioxidant MCI-186 {3-methyl-1-phenyl-2-pyrazolin-5-one}, in preventing the reperfusion injury of the heart by inhibition of PTP opening. Methods and Results: 30 minutes ischemia by left coronary artery (LCA) occlusion and 120 minutes reperfusion in the Wistar rats after pretreatment with MCI-186, 10 mg/kg/iv infusion starting from 30 minutes before LCA occlusion resulted in, (a) less area of myocardial infarction (19.2% Vs 61.6%, MCI-186 to control), (b) well maintained myocardial ATP content (P<0.03 to control), (c) decreased mitochondrial swelling and reduced cytochrome C release (d) increased expression of BCl-2 (e) less prevalence of apoptotic cells (14.3% to 2.9%, MCI-186 to control) and (f) reduced DNA fragmentation in the MCI-186 treated group. These cytoprotective effects of MCI-186 are inhibited on opening PTP before MCI-186 treatment with PTP activators lonidamine (10mg/kg/iv) or atractyloside (5mg/kg/iv), but failed to inhibit the protective effects exerted by another antioxidant allopurinol, thus suggesting the PTP inhibiting property is specific for MCI-186. The above results therefore demonstrate to us that, the radical scavenger MCI-186 by inhibiting the opening of PTP prevents the necrosis and cytochrome C release and hence pathological apoptosis.