Objective: Postoperative management after the Norwood procedure is aimed at optimizing systemic oxygen delivery and mixed venous oxygen saturation. High levels of fraction of inspired oxygen and hyperventilation may increase pulmonary blood flow at the expense of systemic flow. This study determines the effects of these interventions on mixed venous saturation and systemic oxygen delivery in postoperative neonates. Methods: We prospectively studied the effects of 100% fraction of inspired oxygen and hyperventilation in 14 neonates (median age 8 days) 1 to 3 days after the Norwood procedure, while they were sedated, paralyzed, and mechanically ventilated. After establishment of baseline conditions (fraction of inspired oxygen = 29% ± 2%, normal ventilation), patients were exposed to each of the 2 interventions in random order. Mixed venous saturation was measured through a transthoracic line in the superior vena cava. Oxygen excess factor (Ω = systemic oxygen delivery/oxygen consumption) was used as an indicator of systemic oxygen delivery. Results: High levels of fraction of inspired oxygen produced significant increases from baseline in systemic saturation (90% ± 1% vs 80% ± 1%, P < .01), mixed venous saturation (54% ± 3% vs 44% ± 2%, P < .01), and oxygen excess factor (2.6% ± 0.2% vs 2.3 ± 0.2%, P < .01), but there was no change in arteriovenous saturation difference or blood pressure. Hyperventilation resulted in no changes in systemic or mixed venous saturation, arteriovenous saturation difference, oxygen excess factor, or blood pressure. Conclusions: High levels of fraction of inspired oxygen can improve mixed venous oxygen saturation and systemic oxygen delivery after the Norwood procedure. Hyperventilation does not change either mixed venous saturation or oxygen delivery. Management protocols aimed at minimizing the fraction of inspired oxygen and carefully controlling ventilation may not be warranted.