Primary creation of a bidirectional cavopulmonary shunt (BCPS), which provides a stable in-series circulation, might improve survival in patients with hypoplastic left heart syndrome. However, pulmonary vascular immaturity and high pulmonary vascular resistance must be overcome to achieve a successful primary neonatal BCPS. This study tested the hypothesis that a novel mechanical lung assist (MLA) system would permit a primary BCPS in juvenile pigs. A BCPS (1(1/2) ventricle repair physiology) was created in nine 4-5-week-old pigs (mean weight 17.9 kg), followed by MLA with a miniature centrifugal pump and a hand-made double-lumen cannula for 2 hours. Systemic and cerebral hemodynamic and metabolic data were evaluated. A mean BCPS flow of 331 +/- 56 ml/min was obtained with a mean pump speed of 3899 +/- 306 rpm at 30 minutes after MLA initiation. Adequate oxygenation, ventilation, and hemodynamics were maintained. Transcranial Doppler ultrasound demonstrated consistent pre- and postoperative peak systolic and diastolic velocities of the middle cerebral artery, indicating sustained cerebral perfusion pressure. This study demonstrated that the MLA is able to sustain a high-resistance BCPS and provides a strategy or rationale for developing a primary neonatal cavopulmonary connection in appropriately selected neonates with congenital heart disease.