The primary objective of this study was to evaluate the hemodynamic effects of dexmedetomidine (DEX) infusion on critically ill neonates and infants with congenital heart disease (CHD). The secondary objective of the study was to evaluate the safety and efficacy profile of the drug in this patient population. A retrospective observational study was conducted in the cardiovascular intensive care unit (CVICU) of a single tertiary care university children’s hospital. The charts of all neonates and infants who received DEX in the authors’ pediatric CVICU between August 2009 and June 2010 were retrospectively reviewed. The demographic data collected included age, weight, sex, diagnosis, and Risk Adjustment in Congenital Heart Surgery (RACHS-1) score. To evaluate the hemodynamic effects of DEX, physiologic data were collected including heart rate, mean arterial pressure (MAP), inotrope score, near-infrared spectroscopy, and central venous pressure (CVP). To assess the efficacy of DEX, the amount and duration of concomitant sedation and analgesic infusions over a period of 24 h were examined together with the number of rescue boluses. The potential side effects evaluated in this study included nausea, vomiting, abdominal distension, dysrhythmias, neurologic abnormalities, seizures, and signs and symptoms of withdrawal. During the study period, 50 neonates and infants received DEX for a median period of 78 h (range, 40–290 h). These patients had an average age of 3.53 ± 2.64 months and a weight of 4.85 ± 1.67 kg. Whereas 34 patients (68%) received DEX after surgery for CHD, 15 patients (30%) received DEX after heart transplantation. Of these 50 infants, 10 (20%) had a single-ventricle anatomy, whereas 13 (26%) had a risk adjustment score (RACHS-1) in the category of 4–6. The median CVICU stay was 29 days (range, 8–69 days). Despite a significant decrease in heart rate, MAP, inotrope score, and CVP, all the patients remained hemodynamically stable during DEX infusion. There was no substantial difference in major hemodynamic variables between neonates and infants, single- and two-ventricle repair, RACHS 4–6 and RACHS 1–3 categories for patients undergoing surgery, or patients undergoing heart transplantation and patients undergoing other surgical procedures. Dexmedetomidine infusion for neonates and infants with heart disease is safe from a hemodynamic standpoint and can reduce the concomitant dosing of opioid and benzodiazepine agents. Furthermore, DEX infusion may be useful for reducing vasopressor agent dosing in children with catecholamine-refractory cardiogenic shock.