During early myocardial ischemia, the myocytes are loaded with Na⁺, which in turn leads to Ca²⁺ overload and cell death. The pathway of the Na⁺ influx has not been fully elucidated. The aim of the study was to quantify the Na⁺ inward current through sarcolemmal K_ATP channels ( I_KATP,Na) in anoxic isolated cardiomyocytes at the actual reversal potential ( V_rev) and to estimate the contribution of this current to the Na⁺ influx in the ischemic myocardium. I_KATP,Na was determined in excised single channel patches of mouse ventricular myocytes and macropatches of Xenopus laevis oocytes expressing SUR2A/Kir6.2 channels. In the presence of K⁺ ions, the respective permeability ratios for Na⁺ to K⁺ ions, P_Na/ P_K, were close to 0.01. Only in the presence of Na⁺ ions on both sides of the membrane was I_KATP,Na similarly large to that calculated from the permeability ratio P_Na/ P_K, indicative of a Na⁺ influx that is largely independent of the K⁺ efflux at V_rev. With the use of a peak K_ATP channel conductance in anoxic cardiomyocytes of 410 nS, model simulations for a myocyte within the ischemic myocardium showed that the amplitude of the Na⁺ influx and K⁺ efflux is even larger than the respective fluxes by the Na⁺-K⁺ pump and all other background fluxes. These results suggest that during early ischemia the Na⁺ influx through K_ATP channels essentially contributes to the total Na⁺ influx and that it also balances the K⁺ efflux through K_ATP channels.