AbstractConcern over myocardial damage from simultaneous arterial (antegrade) and coronary sinus (retrograde) perfusion has led to alternating between these delivery routes to maximize their individual benefits. Based upon predominant retrograde drainage via Thebesian veins, this study: (1) confirms experimentally the safety of simultaneous arterial and coronary sinus perfusion; and (2) reports initial clinical application of this combined strategy in 155 consecutive patients.Experimental:Five mini‐pigs (25 to 30 kg) underwent 1 hour of aortic clamping with simultaneous aortic and coronary sinus perfusion at 200 mUmin with normal blood (37°C) before and after 30 minutes of perfusion with either warm (37°C) or cold (4°C) blood cardioplegia. Coronary sinus pressure was always less than 30 mmHg. There was no right or left ventricular edema, lactate production, or lipid peroxidation as transmyocardial and myocardial conjugated dienes were unaltered, and postbypass recovered left ventricular end‐systolic elastance (conductance catheter) and preload recruitable stroke work Index 101%± 3% and 109%± 90%, respectively.Clinical:Simultaneous arteriaVcoronary sinus perfusion was used in 155 consecutive high risk patients (New York Heart Association Class III to IV) undergoing isolated coronary artery bypass grafting (CABG) (n = 109) and CABG + valve replacementlrepair or aneurysm (n = 46). Included were 16 patients in cardiogenic shock and 24 undergoing reoperation. Mean aortic clamping time averaged 90 ± 4 minutes (range 30 to 207), with 3.5 ± 0.1 grafts per patient; all anastomoses were performed with the aorta clamped. Cold intermittent blood cardioplegia was used for distal anastomoses and valve implantationhepair in 123 patients, and warm continuous blood cardioplegia was used in 32 patients. Following a warm cardioplegic reperfusate, all patients received warm non‐cardioplegic blood perfusion simultaneously via grafts and coronary sinus. Coronary sinus pressure was always less than 40 mmHg. Of 18 patients requiring postoperative mechanical circulatory support (IABP), 16 had IABP placed preoperatively for cardiogenic shock. There were three postoperative myocardial infarctions (2%), and six patients died (3.9% mortality).Conclusion:These experimental and clinical findings overcome perceived concerns about myocardial damage from simultaneous arterial and coronary sinus perfusion, and suggest this approach may add to the armamentarium of cardioprotective strategies. (J Card Surg