A clinical trial of nifedipine, a calcium antagonist, in cardioplegic solution was performed based on previous laboratory data demonstrating improved postischemic performance in dogs. During a 12 month interval, 47 patients at increased risk had cardiac operations under a protocol in which a standard cardioplegic solution was used on the same solution with the addition of 275 μg/L of nifedipine. The protocol included formal criteria for entrance into the study, serial radionuclide ventriculograms, 24 hour Holter electrocardiographic (ECG) recordings, creatine kinase MB isoenzyme (CK-MB) analyses, technetium 99 myocardial pyrophosphate scans, and intraoperative and postoperative hemodynamic assessment. Thirty of the 47 received nifedipine and 17 received cardioplegic solution only. The two groups were similar for symptoms, anginal and left ventricular function classifications, sex, age, preoperative hemodynamic status, rate of premature ventricular contractions (PVCs), ischemic time-myocardial temperature integrals, and distribution by operation. The results show a difference (p <0.05) between the cardioplegia-only and the cardioplegia plus nifedipine groups immediately following cessation of cardiopulmonary bypass with respect to cardiac index (2.2 ± 0.2 versus 2.8 ± 0.2), stroke volume (49 ± 5 versus 67 ± 5), left ventricular stroke work index (26 ± 2 versus 34 ± 3), right ventricular stroke work index (4.7 ± 0.6 versus 7.0 ± 0.8), pulmonary vascular resistance (228 ± 51 versus 116 ± 18), and total peripheral resistance (1,809 ± 311 versus 1,214 ± 115). The integrals of the concentration of the CK-MB over 1 to 87 hours after operation were 411 X 103 ± 226 X 103 for the cardioplegia-only group and 216 X 103 ± 33 X 103 mIU. hr/ml (p <0.01) for the nifedipine-treated group. Three of 14 cardioplegia-only patients had a change from normal to distinctly abnormal by myocardial scan while none of the 19 nifedipine-treated patients had this change. Four deaths (24%) occurred in the cardioplegia-only group and seven (23%) in the nifedipine-treated group. The incidence of severe myocardial postischemic injury resulting in either hospital death or survival after intensive treatment was 29% (5/17) for the group receiving cardioplegia alone and 20% (6/30) for the nifedipine plus cardioplegia group. The use of nifedipine in cardioplegic solution improved hemodynamic function immediately after bypass, caused less myocardial enzyme release, and probably decreased the incidence of myocardial injury as determined by the pyrophosphate scans. It is concluded that nifedipine is a useful adjunct to current cardioplegic solutions.