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Introduction: Myocardial protection with cardioplegia is a crucial approach to mitigate myocardial damage during coronary bypass grafting surgery (CABG) with cardiopulmonary bypass (CPB). The major component of the del Nido cardioplegia solution, Plasma-Lyte A, is difficult to obtain in Iran due to high cost. The objective of the current study was to study if the lactated Ringer’s solution as the base for del Nido solution (LR DN) usage is a viable option as a substitute for Plasma-Lyte A in adult patients presenting for CABG surgery. Study design and methods: The present prospective, randomized, blinded study was performed on 18–75-year-old patients ejection fraction (EF) > 35% undergoing CABG with CPB. Patients were randomly allocated to LR DN (modified del Nido cardioplegia) and PL DN (standard del Nido cardioplegia solution) groups. Serum level of cardiac troponin I (cTnI), the type and dosage of inotrope agents, EF, rate of arrhythmia after clamp removal and lactate level were measured and compared between patients of LR DN and PL DN groups. Results: 109 patients were recruited. There were no statistically significant differences between groups for cardiopulmonary bypass times, cardiac enzymes, transfusion requirements, and arterial blood gases. There was no mortality for study patients. Postoperative serum levels of cTnI among patients in the LR DN group was significantly higher than patients of the PL DN group after ICU admission and 24 h post-ICU. Also, more patients needed epinephrine administration in the operating room in the LR DN group (29.8% vs. 11.5%; p: 0.019 vs. PL DN group). Conclusion: We concluded that the standard del Nido cardioplegia solution offers better myocardial protection compared with Ringer’s lactate-based del Nido cardioplegia in adult patients undergoing CABG with CPB. We recommend using standard del Nido cardioplegia with a PL base for patients presenting for CABG surgery.