BACKGROUND: Parameters of cardiopulmonary exercise testing were recently identified as strong predictors of mortality in adults with congenital heart disease. We hypothesized that combinations of cardiopulmonary exercise testing parameters may provide optimal prognostic information on midterm survival in this population. METHODS AND RESULTS: A total of 1375 consecutive adult patients with congenital heart disease (age, 33±13 years) underwent cardiopulmonary exercise testing at a single center over a period of 10 years. Peak oxygen consumption (peak V(O(2))), ventilation per unit of carbon dioxide production (V(E)/V(O(2)) slope), and heart rate reserve were measured. During a median follow-up of 5.8 years, 117 patients died. Peak V(O(2)), heart rate reserve, and V(E)/V(O(2)) slope were related to midterm survival in adult patients with congenital heart disease. Risk of death increased with lower peak V(O(2)) and heart rate reserve. A higher V(E)/V(O(2)) slope was also related to increased risk of death in noncyanotic patients, whereas the V(E)/V(O(2)) slope was not predictive of mortality in cyanotic patients. The combination of peak V(O(2)) and heart rate reserve provided the greatest predictive information after adjustment for clinical parameters such as negative chronotropic agents, age, and presence of cyanosis. However, the incremental value of these exercise parameters was reduced in patients with peak respiratory exchange ratio <1.0. CONCLUSIONS: Cardiopulmonary exercise testing provides strong prognostic information in adult patients with congenital heart disease. Prognostication should be approached differently, depending on the presence of cyanosis, use of rate-lowering medications, and achieved level of exercise. We provide 5-year survival prospects based on cardiopulmonary exercise testing parameters in this growing population.