Despite the use of cold blood potassium (CBK) cardioplegia, the severely impaired myocardium and/or long ischemia time continue to be a challenge. Because of the association of Ca++ with cell injury and death, the use of Ca++ entry blockers is logical. Investigation of cold blood diltiazem (CBD) revealed no advantages over CBK cardioplegia. The combination of potassium and diltiazem is appropriate because of their different mechanisms of action. Ten dogs had 1 hour of myocardial ischemia with topical ice (temperature 7 degrees +/- 2 degrees C) after coronary perfusion with 200 ml of cold blood (5 degrees +/- 1 degree C) containing potassium (30 mEq/L) and diltiazem (400 micrograms/kg). Eight dogs had 2 hours of ischemia after perfusion with 200 ml of cold blood containing potassium (30 mEq/L) and diltiazem (200 micrograms/kg) and reperfusion every 30 minutes with 100 ml of cold blood containing KCl (30 mEq/L) and diltiazem (100 micrograms/kg). Six dogs received the same treatment as the previous group except that diltiazem was increased to 1,600 micrograms/kg for all four perfusions. Baseline studies were repeated after 60 minutes of reperfusion without the use of Ca++ or inotropic agents. Heart rate, peak systolic pressure, velocity of the contractile element (Vce), maximum velocity of contractile element (Vmax), peak +dp/dt, peak -dp/dt, dp/dt over common peak isovolumic pressure, left ventricular compliance, stiffness and elasticity, and heart water were unchanged from control. Coronary vascular resistance was unchanged in Groups 1 and 2 but declined in Group 3. Creatine phosphate was preserved during ischemia; adenosine triphosphate (ATP) declined. With reperfusion there was continued fall in ATP, ADP, and the adenosine pool. Ultrastructure was well preserved. In 16 of 24 dogs defibrillation was not required, whereas all 48 dogs with CBK and all 13 with CBD required defibrillation. These data suggest that the addition of diltiazem to CBK provides more effective cardioplegia (preservation of creatine phosphate), although ATP and the adenosine pool continued to decline with reperfusion.