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PURPOSE The hemodynamic gain index (HGI) and cardiorespiratory fitness (CRF) are parameters assessed during cardiopulmonary exercise testing (CPX). The association between the HGI and cardiovascular disease (CVD) mortality is uncertain. We evaluated the association between the HGI and CVD mortality risk using a prospective study. METHODS The HGI was calculated using heart rate (HR) and systolic blood pressure (SBP) measured in 1634 men aged 42-61 yr during CPX, using the formula: [(HRpeak× SBPpeak) - (HRrest × SBPrest)]/(HRrest × SBPrest). Cardiorespiratory fitness was directly measured using a respiratory gas exchange analyzer. RESULTS During a median (IQR) follow-up of 28.7 (19.0, 31.4) yr, 439 CVD deaths occurred. The risk of CVD mortality decreased continuously with the increasing HGI (P value for nonlinearity = .28). Each unit higher HGI (1.06 bpm/mm Hg) was associated with a decreased risk of CVD mortality (HR = 0.80: 95% CI, 0.71-0.89), which was attenuated after further adjustment for CRF (HR = 0.92: 95% CI, 0.81-1.04). Cardiorespiratory fitness was associated with CVD mortality and the association remained after adjustment for the HGI: (HR = 0.86: 95% CI, 0.80-0.92) per each unit (MET) higher CRF. Addition of the HGI to a CVD mortality risk prediction model improved risk discrimination (C-index change = 0.0285; P < .001) and reclassification (net reclassification improvement = 8.34%; P < .001). The corresponding values for CRF were a C-index change of 0.0413 (P < .001) and a categorical net reclassification improvement of 14.74% (P < .001). CONCLUSIONS The higher HGI is inversely associated with CVD mortality in a graded fashion, but the association is partly dependent on CRF levels. The HGI improves the prediction and reclassification of the risk for CVD mortality.