Introduction: Myocardial edema is a clinically relevant problem found in post-ischemic reperfused hearts. The objective of this study was to understand the effects of hetastarch-supplemented cardioplegia on post-ischemic edema and cardiac function. Materials and methods: Swine hearts were arrested with either St. Thomas Hospital cardioplegia with (n = 6) or without (n = 7) 1.5% hetastarch. Following hypothermic global ischemia, hearts were crystalloid reperfused in a four-chamber isolated working mode. Results: Hetastarch decreased myocardial water content gains after three hours of reperfusion (control versus hetastarch, hour 0: 67 ± 5% versus 67 ± 3%, NS; hour 3: 82 ± 2% versus 78 ± 1%, p = 0.1). Post-ischemic control group left ventricular end-diastolic pressures were elevated after 1 h (in mm Hg, hour 0: 13 ± 2, hour 1: 19 ± 3, hour 2: 19 ± 3, hour 3: 20 ± 2) but remained stable (<16 mm Hg) in the hetastarch group. Post-reperfusion creatine phosphokinase perfusate levels in the hetastarch treated hearts were decreased (control: 1.6 IU/l/g versus hetastarch: 0.6 IU/l/g, p = 0.15). Discussion/conclusions: Hetastarch treatment delayed myocardial edema development and attenuated myocardial creatine kinase efflux, thereby preserving diastolic function.