Background -Preoperative brain injury is common in neonates with transposition of the great arteries(TGA). The objective of this study is to determine risk factors for preoperative brain injury in neonates with TGA. Methods and Results -Twenty-nine term neonates with TGA were studied with MRI before cardiac surgery in a prospective cohort study. Twelve patients(41%) had brain injury on preoperative MRI, and all injuries were focal or multifocal. None of the patients had birth asphyxia. Nineteen patients(66%) required preoperative balloon atrial septostomy(BAS). All patients with brain injury had BAS(12 of 19; risk difference, 63%; 95%confidence interval, 41 to 85; P=0.001). As expected on the basis of the need for BAS, these neonates had lower systemic arterial hemoglobin saturation(SaO2)(P=0.05). The risk of injury was not modified by the cannulation site for septostomy(umbilical versus femoral, P=0.8) or by the presence of a central venous catheter(P=0.4). Conclusions -BAS is a major identifiable risk factor for preoperative focal brain injury in neonates with TGA. Imaging characteristics of identified brain injuries were consistent with embolism; however, the mechanism is more complex than site of vascular access for BAS or exposure to central venous catheters. These findings have implications for the indications for BAS, timing of surgical repair, and use of anticoagulation in TGA. Background-Preoperative brain injury is common in neonates with transposition of the great arteries (TGA). The objective of this study is to determine risk factors for preoperative brain injury in neonates with TGA. Methods and Results-Twenty-nine term neonates with TGA were studied with MRI before cardiac surgery in a prospective cohort study. Twelve patients (41%) had brain injury on preoperative MRI, and all injuries were focal or multifocal. None of the patients had birth asphyxia. Nineteen patients (66%) required preoperative balloon All expected with the brain injury had BAS (12 of 19; risk difference, 63%; 95% confidence interval, 41 to 85; P = 0.001) neonates had lower systemic arterial hemoglobin saturation (SaO2) (P = 0.05). The risk of injury was not modified by the cannulation site for septostomy (umbilical versus femoral, P = 0.8) or by the presence of a central venous catheter (P = 0.4). Conclusions -BAS is a major identifiable risk factor for preoperative focal brain injury in neonates with TGA. Imaging characteristics of identified brain injuries were consistent with embolism; however, the mechanism is more complex than site of vascular access for BAS or exposure to central venous catheters. These findings have implications for the indications for BAS, timing of surgical repair, and use of anticoagulation in TGA.