The goal of the present study was to assess how genetic loss of microsomal prostaglandin E(2) synthase-1 (mPGES-1) affects acute cardiac ischemic damage after coronary occlusion in mice. Wild type (WT), heterozygous (mPGES-1(+/-)), and homozygous (mPGES-1(-/-)) knockout mice were subjected to left coronary artery occlusion. At 24h, myocardial infarct (MI) volume was measured histologically. Post-MI survival, plasma levels of creatine phosphokinase (CPK) and cardiac troponin-I, together with MI size, were similar in WT, mPGES-1(+/-) and mPGES-1(-/-) mice. In contrast, post-MI survival was reduced in mPGES-1(-/-) mice pretreated with I prostanoid receptor (IP) antagonist (12/16) compared with vehicle-treated controls (13/13 mPGES-1(-/-)) together with increased CPK and cardiac troponin-I release. The deletion of mPGES-1 in mice results in increased prostacyclin I(2) (PGI(2)) formation and marginal effects on the circulatory prostaglandin E(2) (PGE(2)) level. We conclude that loss of mPGES-1 results in increased PGI(2) formation, and in contrast to inhibition of PGI(2), without worsening acute cardiac ischemic injury.