Background: Cardiopulmonary bypass-induced oxidative stress initiates inflammation that can damage the myocardium. This study tested whether cardioplegia enriched with the intermediary metabolite and antioxidant pyruvate dampens postbypass myocardial inflammation. Methods: Pigs were maintained on cardiopulmonary bypass while their hearts were arrested for 60 minutes with 4:1 blood:crystalloid cardioplegia, in which the crystalloid contained 188 mM glucose ± 24 mM pyruvate. Pigs were weaned from bypass after 30 minutes of whole blood reperfusion and recovered for 4 hours. Glutathione (GSH) and glutathione disulfide (GSSG) were measured in coronary sinus plasma to indirectly monitor myocardial GSH redox state (GSH/GSSG). Left ventricular myocardium was sampled 4 hours after cardiopulmonary bypass for analyses of C-reactive protein, matrix metalloproteinases 2 and 9 and tissue inhibitor of metalloproteinase-2 (TIMP-2), and to assess neutrophil infiltration by histology and myeloperoxidase assay. Results: Coronary sinus GSH/GSSG fell 70% after cardiopulmonary bypass with control cardioplegia, but pyruvate cardioplegia produced a robust increase in coronary sinus GSH/GSSG that persisted for 4 hours after bypass. Myocardial C-reactive protein content increased 5.6-fold after control bypass, and neutrophil infiltration and myeloperoxidase activity also increased, but pyruvate-fortified cardioplegia prevented these inflammatory effects. Control cardioplegia lowered myocardial TIMP-2 content by 59% and increased matrix metalloproteinase-9 activity by 35% versus nonbypass sham values, but pyruvate cardioplegia increased TIMP-2 content ninefold versus control cardioplegia and prevented the increase in matrix metalloproteinase-9. Matrix metalloproteinase-2 was not affected by bypass ± pyruvate. Conclusions: Pyruvate-enriched cardioplegia dampens cardiopulmonary bypass-induced myocardial inflammation. Increased GSH/GSSG and TIMP-2 may mediate pyruvate's effects.