Background The use of cardioplegia solution is aimed to avoid myocardial muscle damage, leading to poor contraction and abnormal increased release of cardiac biomarkers enzymes during cardiac arrest. It remains the primary method for myocardial protection against ischemia–reperfusion injury during cardiac surgery. Cardioplegia was first presented as an agent for hypothermic hyperkalemic arrest. Blood was then introduced as a vehicle to convey potassium to the heart. Histidine–tryptophan–ketoglutarate solution is safe and used as a single dose that can last for up to 3 h. Comparison between custodiol cardioplegia and cold blood cardioplegia still remains a big debate till now. Objective To compare the clinical outcomes of custodiol solution with cold blood cardioplegia in mitral valve replacement (MVR) with cardiac ejection fraction less than 45%. Patients and methods This single‑center randomized prospective study was carried out from January 2018 till June 2019 at Ain Shams University hospitals. Overall, 65 patients with poor left ventricular function undergoing mitral valve replacement were divided randomly according to type of myocardial protection into two groups: group A included 30 patients who received custodiol cardioplegia, and group B included 35 patients who received cold blood cardioplegia. Data from each group were collected and compared with each other. Results Baseline demographic and intraoperative data showed no significant difference between the two groups. The need for inotropic support, length of mechanical ventilation, and ICU stay were statistically nonsignificant between the two groups. There was a statistically significant difference regarding the rhythm upon declamping [ventricular fibrillation (VF) in 17 (56.7%) cases in group A and nine (25.7%) cases in group B (P=0.016)], and also there was a significant difference in times of defibrillation cardioversion (DC) shock given after declamping (P=0.005). Overall mortality shows a statistically nonsignificant difference. There is a significant difference in postoperative echo assessment for both groups [ejection fraction in group A: 53.17±7.73 compared with 49.06±7.170 in group B (P=0.031)], and there is also a difference in hemoglobin postoperatively, with 10.35±0.843 in group A compared with 10.88±0.798 in group B (P=0.013). Conclusion Cardiac arrest using custodiol cardioplegia is a good choice in mitral valve replacement with the advantage of giving only one dose of cardioplegia without interruption of the operation, and also it gives good postoperative echo results than cold blood cardioplegia. Its disadvantages are lower hemoglobin levels postoperatively and hyponatremia during bypass in comparison with cold blood cardioplegia.