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Objectives: We performed a regional volumetric study of the brain using 3-dimensional magnetic resonance imaging in infants with congenital heart disease to search for variables in anatomic development of the brain that may be associated with functional impairment., Methods: Forty infants with congenital heart disease-17 infants with single ventricle physiology, 5 with transposition of great arteries, and 18 with ventricular septal defect-were studied prospectively by 3-dimensional magnetic resonance imaging of the brain several months after heart surgery., Results: The global volume of gray matter was significantly reduced in the patients with congenital heart disease compared with normal controls (P < .001), whereas no significant difference in the volume of white matter was observed. Further, the decrease in gray matter volume was more apparent in the frontal lobe than in the temporal lobe, especially in infants with single ventricle physiology or transposition of the great arteries. Multivariate analysis revealed that preoperative hypoxia is strongly associated with decreased frontal gray matter volume (P < .01), as well as a diagnosis of hypoplastic left heart syndrome (P < .05). Of note, frontal gray matter volume, which includes the motor area, correlated weakly with psychomotor developmental index scores (P < .01)., Conclusions: Brain developmental impairment occurs in many infants with congenital heart disease, especially in those who have preoperative hypoxia and critical congenital heart disease. This quantitative volumetric study encourages larger scale and longitudinal follow-up to elucidate the significance of impaired neuroanatomic development on functional outcome.