Background The del Nido (DN) cardioplegia solution has been widely used in paediatric open-heart surgery for years; however, its application in adult open-heart surgery has not yet gained sufficient popularity. We investigated the safety and efficiency of the DN cardioplegia solution versus the traditional crystalloid cardioplegia solution [St. Thomas' Hospital (STH) cardioplegia solution] in adult patients undergoing coronary artery bypass grafting (CABG). Methods A retrospective comparative analysis of 200 consecutive patients undergoing isolated on-pump CABG between April 2016 and September 2017 was performed. Patients were divided into two groups: DN group (n = 100) and STH group (n = 100). Groups were compared with regard to perioperative clinical outcomes, and the safety and efficiency of the DN cardioplegia solution in CABG surgery were evaluated. Results In the DN group, mean aortic cross-damp, cardiopulmonary bypass, and total operation times were significantly shorter than in the STH group. After the release of the aortic cross-clamp, the requirement for intraoperative defibrillation was significantly less in the DN group. There were no significant differences between the groups in terms of the levels of perioperative cardiac biomarkers (including creatine kinasemyocardial band and troponin I), major postoperative adverse events, and in-hospital mortality. Conclusions This study revealed that the use of the DN cardioplegia solution in adult patients undergoing isolated CABG provides significantly shorter aortic cross-clamp, cardiopulmonary bypass, and total operation times compared with the traditional cardioplegias solution. The DN solution could be used as a safe and efficient alternative to the traditional cardioplegia solutions in CABG surgery. C1 [Cayir, Mustafa Cagdas] Pamukkale Univ, Fac Med, Dept Cardiovasc Surg, Denizli, Turkey. [Yuksel, Ahmet] Abant Izzet Baysal Univ, Fac Med, Dept Cardiovasc Surg, Golkoy Campus, TR-14280 Bolu, Turkey.