Objectives: Congenital diaphragmatic hernia (CDH) remains a significant cause of neonatal morbidity and mortality. Summary of Background Data: Previous studies have suggested that hospital volume is an independent predictor of in-hospital mortality. We sought to validate this effect using a large national database incorporating 37 free-standing children's hospitals in the United States. Methods: Infants who underwent repair of CDH from 2000 to 2008 at Pediatric Health Information Systems-member hospitals were evaluated. Hospitals were categorized by tertiles into low-volume (≤6 cases/yr), medium-volume (6-10 cases/yr), and high-volume (>10 cases/yr). Using generalized linear mixed models with random effects, we computed the risk-adjusted odds ratio of mortality by yearly hospital volume of CDH repair, after adjustment for salient patient and hospital characteristics. Results: There were 2203 infants who underwent repair with an overall survival of 82%. Average yearly hospital volume of CDH repair varied from 1.4 to 17.5 cases per year. Smaller birthweight (adjusted odds ratio [aOR]: 0.56 per kg, P < 0.001), year of birth (P < 0.001), chromosomal abnormalities (aOR: 3.83, P < 0.01), longer time to repair (aOR: 1.12 per week, P < 0.05), the thoracic approach for repair (P < 0.02), and requirement for extracorporeal membrane oxygenation (aOR: 10.31, P < 0.0001), or inhaled nitric oxide (aOR: 5.25, P < 0.0001) were each independently associated with mortality. Compared with low-volume hospitals, medium-volume (aOR: 0.56, P < 0.05) and high-volume (aOR: 0.44, P < 0.01) hospitals had a significantly lower mortality. The rate of extracorporeal membrane oxygenation use at each facility was not independently associated with mortality. Conclusions: This large study suggests that hospitals which perform high volumes of CDH repair achieve lower in-hospital mortality. These data support the paradigm of regionalized centers of excellence for the management of infants with this morbid condition.