© 2015 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. Objective: Neonatal cardiac surgery with cardiopulmonary bypass is often complicated by morbidity associated with inflammation and low cardiac output syndrome. Hydrocortisone "stress dosing" is reported to provide hemodynamic benefits in some patients with refractory shock. Development of cardiopulmonary bypass-induced adrenal insufficiency may provide further rationale for postoperative hydrocortisone administration. We sought to determine whether prophylactic, postoperative hydrocortisone infusion could decrease prevalence of low cardiac output syndrome after neonatal cardiac surgery with cardiopulmonary bypass. Design: Double-blind, randomized control trial. Setting: Pediatric cardiac ICU and operating room in tertiary care center. Patients: Forty neonates undergoing cardiac surgery with cardiopulmonary bypass were randomized (19 hydrocortisone and 21 placebo). Demographics and known risk factors were similar between groups. Interventions: After cardiopulmonary bypass separation, bolus hydrocortisone (50 mg/m2) or placebo was administered, followed by continuous hydrocortisone infusion (50 mg/m2/d) or placebo tapered over 5 days. Adrenocorticotropic hormone stimulation testing (1 μg) was performed before and after cardiopulmonary bypass, prior to steroid administration. Blood was collected for cytokine analysis before and after cardiopulmonary bypass. Measurements and Main Results: Subjects receiving hydrocortisone were less likely to develop low cardiac output syndrome (5/19, 26% vs 12/21, 57%; p = 0.049). Hydrocortisone group had more negative net fluid balance at 48 hours (-114 vs -64 mL/kg; p = 0.01) and greater urine output at 0-24 hours (2.7 vs 1.2 mL/kg/hr; p = 0.03). Hydrocortisone group weaned off catecholamines and vasopressin sooner than placebo, with a difference in inotrope-free subjects apparent after 48 hours (p = 0.033). Five placebo subjects (24%) compared with no hydrocortisone subjects required rescue steroids (p = 0.02). Thirteen (32.5%) had adrenal insufficiency after cardiopulmonary bypass. Patients with adrenal insufficiency randomized to receive hydrocortisone had lower prevalence of low cardiac output syndrome compared with patients with adrenal insufficiency randomized to placebo (1/6 vs 6/7, respectively; p = 0.02). Hydrocortisone significantly reduced proinflammatory cytokines. Ventilator-free days, hospital length of stay, and kidney injury were similar. Conclusions: Prophylactic, postoperative hydrocortisone reduces low cardiac output syndrome, improves fluid balance and urine output, and attenuates inflammation after neonatal cardiopulmonary bypass surgery. Further studies are necessary to show if these benefits lead to improvements in more important clinical outcomes.