Background. Intramyocyte sodium (Na+) increases during ischemia and reperfusion, which causes myocardial calcium (Ca2+) uptake and leads to myocyte injury or death. This study determines if ischemic preconditioning and myocyte sodium-hydrogen ion (Na+-H+) exchange (NHE) inhibition decreases Na+ gain that otherwise occurs with cardioplegic arrest and reperfusion. Methods. Pigs had 1 hour of cardioplegic arrest followed by reperfusion. Group 1 had no intervention (controls). Group 2 received dimethyl amiloride (DMA, an NHE inhibitor), and group 3 had ischemic preconditioning before cardioplegic arrest. Precardioplegia to postreperfusion change in intramyocyte ion content was measured with atomic absorption spectrometry. The time to initial electrical activity and number of defibrillations needed to establish an organized rhythm postreperfusion were used as electrophysiologic variables to measure ischemia-reperfusion injury. Results. Intramyocyte Na+ content for group 1 increased from 45.9 ± 6.7 to 61.9 ± 22.5 μmol/g (p = 0.02). Group 2 had an insignificant decrease in intramyocyte Na+ of 27.7 ± 19.58 μmol/g (p = 0.06), and group 3 had an insignificant decrease of 10.8 ± 46.33 μmol/g (p = 0.48). Interstitial water increased significantly in all groups, but there were no significant increases in intramyocyte water content. Electrophysiologic recovery was similar for all three groups. Conclusions. The NHE inhibition and ischemic preconditioning each eliminated the increase in intramyocyte Na+ content that otherwise occurred with cardioplegic arrest and reperfusion in this porcine model. Because their mechanisms are distinct, it is possible that an additive beneficial effect against ischemia-reperfusion injury can be achieved by using NHE inhibition together with a preconditioning stimulus as prereperfusion therapy. © 2002 by The Society of Thoracic Surgeons.