The response to cardiopulmonary exercise (CPX) in patients with heart failure (HF) with normal left ventricular (LV) ejection fractions (EFs) is not well characterized. To determine if CPX testing could distinguish between patients with HF with normal EFs (>50%; i.e., diastolic HF) and those with decreased EFs (≥50%; i.e., systolic HF), CPX responses were compared between 185 patients with systolic HF (79% men, mean age 62.6 ± 10.9 years) and 43 with diastolic HF (54% men, mean age 67.4 ± 9.8 years) enrolled in a phase II multicenter clinical trial. All patients were evaluated with echocardiography and a standardized CPX test as part of the trial. CPX variables, including oxygen uptake at peak exercise (peak VO2) and the slope of the ventilation/carbon dioxide production ratio (VE/VCO2), were determined and analyzed by core laboratory personnel. Echocardiographic measurements included the LV EF, the E/A ratio, filling time, cavity volumes, right ventricular function, and mitral regurgitation. Patients in the diastolic HF group tended to be older (p <0.08), with more women (p <0.006) and with greater body mass indexes (p <0.02), than those in the systolic HF group. There was no significant difference in the use of β blockers or the incidence of coronary artery disease. Patients with diastolic HF had decreased E/A ratios (0.9 ± 0.4 vs 1.4 ± 1.1, p <0.02, diastolic HF vs systolic HF) and increased filling times (30.4 ± 3.2 vs 26.5 ± 4.7 ms, p <0.01, diastolic HF vs systolic HF). No significant differences in peak VO2 (14.4 ± 1.9 vs 15.6 ± 3.2 ml/kg/min, p = 0.06, diastolic HF vs systolic HF) were observed. The VE/VCO2 ratios for the 2 groups were abnormal and comparable (32 2 ± 7.5 vs 34.0 ± 8.3, p = 0.3, diastolic HF vs systolic HF). In conclusion, the CPX response in patients with diastolic HF and systolic HF is markedly abnormal and indistinguishable with regard to peak VO2 and ventilation despite marked differences in the LV EF.