OBJECTIVE Advancements in the preoperative management of patients with single-ventricle physiology continue to evolve. Previous reports have questioned the benefit of using inhaled nitrogen in single-ventricle patients, suggesting that this therapeutic modality may not provide adequate systemic cardiac output. The objective of this study was to review our institutional experience managing preoperative patients with single-ventricle physiology using a combination of afterload reduction and inhaled hypoxemic therapy. DESIGN, SETTING, AND PATIENTS This is a retrospective review of 49 consecutive single-ventricle patients admitted preoperatively between July 2004 and January 2009, to the cardiac intensive care unit at Children's Hospital of Pittsburgh who underwent single-ventricle palliation, and treated preoperatively with milrinone and inhaled nitrogen. Therapeutic interventions and indirect indicators of cardiac output were collected on day of admission (time 0) and compared with those collected on the morning of surgery (time 1); data included clinical assessment, hemodynamic measurements, and laboratory values. RESULTS When comparing time 0 to time 1, there was a statistically significant decrease in lactate (from 2.2 to 1.8 mEq/L [P < 0.001]) and an increase in pH (from 7.36 to 7.41 [P < 0.001]), serum bicarbonate (from 24.16 to 27.55 mmol/L [P < 0.001]) and arterial PaO2 (from 38.10 to 41.82 mm Hg [P = 0.027]). Preoperatively, there were no deaths, and only two patients had an evidence of multiorgan dysfunction on day of surgery (time 1). CONCLUSION Our results suggest that a combination of afterload reduction and hypoxemic therapy was able to maintain an appropriate distribution of the cardiac output in the majority of preoperative patients with single-ventricle physiology. An adequate balance of systemic and pulmonary blood flow was successfully achieved with an increase in arterial PaO2 values.