We sought to assess acute hemodynamic changes after implementation of negative extrathoracic pressure (NEP) in spontaneously breathing ambulatory Fontan patients with symptomatic heart failure. We hypothesized that application of NEP would result in an acute decrease in pulmonary artery pressure. Ten patients with clinical evidence of Fontan failure underwent baseline hemodynamic catheterization while breathing spontaneously. Hemodynamic measurements were then repeated after 30 min of continuous NEP. After 30 min of continuous NEP, 4/10 patients had a decrease in their Fontan pressure by 2 mmHg and one patient had a decrease by 1 mmHg. There were three patients that had an increase in Fontan pressure by 2 mmHg. In 7/10 patients, indexed pulmonary vascular resistance decreased by an average of 31%. In symptomatic Fontan patients with a favorable hemodynamic response to NEP during catheterization, potential benefit of longer-term NEP to improve clinical status should be explored.