BACKGROUND Important in the postoperative management of neonates with single-ventricle complexes, such as hypoplastic left heart syndrome and pulmonary atresia with intact ventricular septum, is the fact that the pulmonary circulation is connected to the systemic circulation via a shunt. The distribution of flow to the pulmonary and systemic vascular beds depends directly on the pulmonary-to-systemic vascular resistance ratio. Changes in this ratio result in alterations in flow that have an impact on survival. RESULTS PICO2 has a potent effect on pulmonary vascular resistance. In this study, the addition of CO2 to inspired gas (PICO2) is assessed as a means of modulating the ratio of pulmonary-to-systemic vascular resistance and thus flow, while avoiding the consequences of hypoventilation. Thirteen neonatal piglets (age, 17 to 30 days) were subjected to atrial septectomy, patch closure of the tricuspid valve, and creation of a 4-mm systemic-to-pulmonary arterial shunt to mimic the physiology of single-ventricle complexes. Pulmonary and systemic flows; aortic, pulmonary artery, and atrial pressures; and arterial blood gases were measured with the addition of different levels of CO2 to the inspired gases (PICO2 = 0 to 35 mmHg). In all animals, pulmonary vascular resistance (PVR) increased in direct correlation with PICO2. In group 1 (n = 8), PVR increased in direct correlation with PICO2 and PACO2, and inversely with respect to pH (r = .98, .74, and .83, respectively). Group 2 animals (n = 5) received infusions of Tham to buffer hydrogen ion and compensate for respiratory acidosis. PVR again increased in direct correlation with FICO2 (r = .97). In both groups, systemic vascular resistance (SVR) was less directly influenced by FICO2 (r = .53). CONCLUSIONS CO2 exerts a vasoactive influence on pulmonary vasculature that is largely independent of SVR and pH. Regulating PICO2 is an effective means of achieving a favorable ratio of pulmonary-to-systemic vascular resistance and thus flow in the fragile physiology encountered in neonates with single-ventricle complexes.