The ventilatory efficiency, minute ventilation (VE)/carbon dioxide production (VCO2), slope consistently provides valuable prognostic information in patients with heart failure (HF). Patients with a higher body mass index (BMI) have demonstrated an improved prognosis in the HF population, a phenomenon that has been termed the "obesity paradox." The purpose of this study was to evaluate the prognostic ability of the VE/VCO2 slope according to BMI in patients with HF. Seven-hundred four patients with HF (555 men, 149 women, mean age 56.8+/-13.4 years, ejection fraction 33.1+/-13.3%) with a BMI>or=18.5 kg/m2 underwent cardiopulmonary exercise testing. Subjects were divided into 3 BMI subgroups (18.5 to 24.9, 25.0 to 29.9, and >or=30 kg/m2). Each subject was tracked for major cardiac events (death, transplantation, left ventricular assist device implantation) for 2 years after testing. There were 86 major cardiac events (71 deaths, 10 transplantations, 5 left ventricular assist device implantations) during the 2-year tracking period (overall annual event rate 8.2%). The VE/VCO2 slope was the strongest prognostic marker in each BMI subgroup. Subjects in the highest BMI group had the lowest mean VE/VCO2 slope and the lowest rate of major cardiac events of the 3 groups. Multivariate Cox regression analysis showed that peak VO2 did not add additional prognostic value to the VE/VCO2 slope and was removed from the regression for each BMI subgroup. In conclusion, the findings of the present study indicate that VE/VCO2 slope maintains prognostic value irrespective of BMI in patients with HF.