Background: Fluid overload contributes to poor outcomes after neonatal cardiac surgery. The optimal strategy to mitigate fluid overload related morbidity is unknown. The utility of prophylactic peritoneal dialysis remains controversial. We aimed to assess the impact of prophylactic peritoneal dialysis on outcomes and hypothesized that prophylactic dialysis would be associated with less fluid overload and improved outcomes in neonates undergoing the arterial switch operation. Methods: A single-center retrospective analysis of 41 consecutive neonates between June 2010 and March 2016 undergoing the arterial switch operation was performed. Fluid balance and other outcomes were compared between those who received peritoneal dialysis (n = 25) and those who did not (n = 16). Results: Demographics were similar between groups, except cardiopulmonary bypass duration, which was significantly longer in the dialysis group (125 ± 20 minutes) compared with the no dialysis group (109 ± 15 minutes; P = .01). Median time to dialysis initiation was 9.1 hours (interquartile range, 7 to 9.8) and median time to termination from cardiac intensive care unit admission was 58.7 hours (interquartile range, 44 to 76.1). Cumulative fluid balance in the dialysis group was significantly more negative compared with the no dialysis group across all 7 postoperative days. In the multivariable analysis, use of dialysis was associated with a 42% reduction in hours of mechanical ventilation (relative risk 0.58; 95% confidence interval, 0.4 to 0.85; P < .01) and a 34% reduction in intensive care unit length of stay (relative risk 0.66; 95% confidence interval, 0.47 to 0.94; P = .02). Utilization of dialysis was associated with lower hospital costs (P < .01). Conclusions: Prophylactic peritoneal dialysis after the arterial switch operation is associated with improved postoperative outcomes without increased hospital costs (Graphical Abstract).