The prognostic value of cardiopulmonary exercise testing (CPX) for mortality risk remains controversial in Fontan patients. Our goal of the present study was to clarify the prognostic value of major CPX variables and the factors determining exercise capacity in a large cohort of Fontan patients. Since 1990, heart rate (HR), oxygen uptake (VO2 ), and ventilatory equivalent for carbon dioxide production (VE/VCO2 ) at peak exercise were determined in 335 Fontan patients (18 ± 5 years old), and the CPX variables were compared with the clinical profile and events. When compared with 209 controls, peak HR (148 ± 24 bpm), VO2 (27 ± 7 mL/kg/minute, 61 ± 15%), and VE/VCO2 (40 ± 8 117 ± 24%) were markedly impaired in the Fontan patients (P < .0001). During a follow-up of 3.1 ± 2.7 years, 62 Fontan pathophysiological-associated events requiring unscheduled hospitalization (USH) occurred, and 24 patients died. All the CPX variables predicted the USH and mortality (P < .001-.0001). On multivariate analysis, in addition to use of diuretics (P = .0007) and low cardiac index (P = .0426), peak VO2 independently predicted the USH (hazard ratio: 0.95 per %, 95% confidence interval: 0.91-0.99, P = .014), while for mortality, multivariate analysis revealed that, in addition to heterotaxy syndrome (P = .0128) and year at first Fontan operation (P = .0532), peak VO2 independently predicted mortality (hazard ratio: 0.88 per %, 95% confidence interval: 0.76-0.98, P = .0217). Fontan patients exhibit markedly impaired CPX variables, and all the major variables, especially peak VO2 , predicted the risk of both morbidity and mortality.