High-flow nasal cannula (HFNC) therapy supports respiratory effort with a minimal elevation in airway pressure. We examined hemodynamic effects of HFNC therapy in a 10-year-old girl with Fontan circulation, in which positive airway pressure has deleterious hemodynamic effects. The HFNC therapy at 30 L/min improved oxygenation without an increase in central venous pressure. It also reduced heart rate, and systemic and pulmonary vascular resistance, and increased cardiac output. In addition, the HFNC therapy improved the cerebral circulation measured by near-infrared spectroscopy. Thus, HFNC therapy may be a potentially useful noninvasive ventilation modality, particularly for patients with Fontan circulation.