A prospective, randomized study was performed on 120 patients undergoing elective coronary bypass grafting to define the effect of the calcium channel blocker diltiazem on perioperative ischemia, arrhythmias, and myocardial function. Patients received a continuous 24-hour perioperative infusion of either diltiazem (0.1 mg/kg per hour, n = 60) or nitroglycerin (1 μg/kg per minute, n = 60). Perioperative monitoring included hemodynamic measurements, three-channel Holter monitoring, repeated assessment of 12-lead electrocardiograms, and analysis of ischemia-specific laboratory parameters (creatine kinase, creatine kinase-MB, and creatine kinase-MB-mass and troponin-T). Global and regional systolic function and diastolic compliance were assessed by means of transesophageal echocardiography. The two groups did not differ with respect to preoperative and operative data. Except for a significant reduction in perioperative heart rate, diltiazem had no influence on hemodynamic parameters. The number (17 ± 9 versus 25 ± 5, p < 0.05) and the duration (69 ± 47 versus 104 ± 87 minutes, p < 0.05) of transient ischemic events were significantly reduced as compared with the nitroglycerin group. In addition, peak values of all assessed laboratory parameters except creatine kinase were significantly lower in the diltiazem group. Patients treated with diltiazem had a lower incidence of perioperative atrial fibrillation (5% versus 18%, p < 0.05) and lower numbers of ventricular premature beats per hour (10 ± 8 versus 19 ± 22, p < 0.05) and ventricular runs per hour (5 ± 17 versus 32 ± 38, p < 0.05). Postoperatively, the percent fractional area of contraction and percent systolic wall thickening of the anterior wall were significantly improved in the diltiazem group but not in the nitroglycerin group. In addition, the postoperative diastolic flow/velocity ratio was significantly lower in the nitroglycerin group than in the diltiazem group (0.949 ± 0.391 versus 1.331 ± 0.475, p < 0.001). It is concluded that perioperative infusion of the calcium antagonist diltiazem has no adverse effect on perioperative hemodynamics and systolic myocardial function and provides potent antiischemic and antiarrhythmic protection in patients undergoing coronary bypass grafting.