In this clinical trial, we evaluated if a short-acting nucleoside, adenosine, as a high-dose bolus injection with blood cardioplegia induces faster arrest and provides better myocardial performance in patients after bypass surgery for coronary artery disease. Forty-three patients scheduled for elective or urgent coronary artery bypass grafting were prospectively recruited in two-arm 1:1 randomized parallel groups to either receive 20 mg of adenosine (in 21 patients) or saline (in 22 patients) into the aortic root during the first potassium-enriched blood cardioplegia infusion. The main outcomes of the study were ventricular myocardial performance measured with cardiac index, right ventricular stroke work index, and left ventricular stroke work index at predefined time points and time to asystole after a single bolus injection of adenosine. Conventional myocardial biomarkers were compared between the two groups at predefined time points as secondary endpoints. Electrocardiographic data and other ad hoc clinical outcomes were compared between the groups. Compared with saline, adenosine reduced the time to asystole (68 (95% confidence interval (95% CI) = 37-100) versus 150 (95% CI = 100-210) seconds, p = 0.005). With myocardial performance, the results were inconclusive, since right ventricular stroke work index recovered better in the adenosine group (p = 0.008), but there were no significant overall differences in cardiac index and left ventricular stroke work index between the groups. Only the post-cardiopulmonary bypass cardiac index was better in the adenosine group (2.3 (95% CI = 2.2-2.5) versus 2.1 (95% CI = 1.9-2.2) L/min/m2, p = 0.016). There were no significant differences between the groups in cardiac biomarker values. A high dose adenosine bolus at the beginning of the first cardioplegia infusion resulted in significantly faster asystole in coronary artery bypass grafting patients but enhanced only partially the ventricular performance.EudraCT number: 2014-001382-26. https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-001382-26/FI.