The relative efficacy and safety of blood-based potassium cardioplegic solutions compared to crystalloid arresting solutions has been a major controversy in the field of intraoperative myocardial protection for cardiac operations. In this study multidose potassium (K+ = 30 mEq/L) blood cardioplegia was compared to multidose potassium crystalloid cardioplegia in a dog model in which hearts were arrested for periods of 4 1/2 and 6 hours. The cardioplegic solution was given as an initial bolus of 500 ml and then as 250 ml doses every 30 minutes of arrest. In the 4 1/2 hour arrest group, six animals received blood cardioplegia, six received a low-sodium crystalloid cardioplegia (modified Roe's solution), and 10 received a high sodium crystalloid cardioplegic solution of our own design. In the 6 hour arrest group, four animals received blood cardioplegia, four received the low-sodium solution, and four received the high-sodium solution. Myocardial temperature was precisely controlled at 27 degrees +/- 1 degree C in all groups. The hearts were reperfused for periods of 2 to 4 hours after the arrest periods and then examined morphologically for injury. The extent of myocardial damage was quantified in 5 mm thick transverse sections through the ventricles by using a tetrazolium enzyme-mapping technique. In the crystalloid groups the hearts arrested for 4 1/2 hours were significantly injured. The percentage (+/- SEM) of necrosis was 12.3 % +/- 5.6% in the low-sodium cardioplegic (modified Roe's) group and 9.3% +/- 3.4% in the high-sodium group. In the 6 hour arrest group the hearts were severely injured, with contracture occurring in all cases. The percentage of necrosis was 56.5% +/- 13% in the low-sodium cardioplegic group and 71.3% +/- 12% in the high-sodium group. In striking contrast all hearts protected with blood cardioplegia failed to show any evidence of tissue damage either on tetrazolium staining or on electron microscopic examination. We conclude that blood cardioplegia offers superior protection to the arrested heart at moderate hypothermia compared to crystalloid cardioplegia.