Background: Various inotropes and inodilators have been utilized to treat low cardiac output syndrome after the arterial switch operation. The use of levosimendan, a calcium sensitizer has been limited in this setting. This study compares the effects of levosimendan with milrinone in managing low cardiac output after the arterial switch operation. Methods: A retrospective, comparative study was conducted in a tertiary care hospital on patients weighing up to 3 kg undergoing the arterial switch operation between January 2017 and January 2022. Patients received a loading dose followed by continuous infusion of either levosimendan or milrinone. Echocardiographic, hemodynamic and biochemical parameters were compared. Results: Forty-three patients received levosimendan and 42 patients received milrinone as the primary test drug. Cardiac index of less than 2.2 L/min/m2 on postoperative day 1 and 2 was found in 9.3% and 2.3% of patients receiving levosimendan versus 26.2% and 11.9% in those receiving milrinone, respectively (P = .04 and .08, respectively). Early lactate-clearance and better central venous oxygen saturations were noted in the levosimendan group. Prevalence of acute kidney injury was higher in the milrinone group (50% vs 28%; P = .03). Use of peritoneal dialysis in the milrinone group versus levosimendan was 31% and 16.3%, respectively (P = .11). There was no difference in hospital mortality between the groups (milrinone, 3; levosimendan, 2, P = .62). Conclusions: Levosimendan is safe and as effective as milrinone to treat low cardiac output syndrome occurring in neonates after the arterial switch operation. In addition we found that levosimendan was renal protective when compared with milrinone.