The purpose of this study was to examine the therapeutic potential of ranolazine, a novel antianginal drug, as an adjunctive therapy to hyperkalemic cardioplegia. Rat hearts were Langendorff-perfused and exposed to 40 minutes of ischemia and 30 minutes of reperfusion without (control) or with cardioplegia or cardioplegia with 50 μmol/L ranolazine. During ischemia, cardioplegia prolonged time to contracture, defined as the time to reach an intraventricular pressure of 20 mm Hg, from 12 ± 1 minute (control) to 25 ± 2 minutes (P < .05). Ranolazine supplement further lengthened the time to contracture to 34 ± 2 minutes (P < .05). Ischemia/reperfusion caused a dramatic elevation in left ventricular end diastolic pressure (LVEDP) during reperfusion. Cardioplegia lessened the LVEDP elevation measured at 30 minutes of reperfusion from 76 ± 3 mm Hg (control) to 32 ± 3 mm Hg (P < .05). The increase in LVEDP was reduced even further to 17 ± 2 mm Hg in hearts receiving cardioplegia plus ranolazine (P < .05). These results suggest that addition of ranolazine during hyperkalemic ischemic cardioplegic arrest is beneficial and provides further protection against contracture.