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Background: Ventilatory efficiency (minute ventilation required to eliminate carbon dioxide, VE/VCO2) during exercise potently predicts outcomes in advanced heart failure with reduced ejection fraction, but its prognostic significance for at-risk individuals with preserved left ventricular systolic function is unclear. We aimed to characterize mechanistic determinants and prognostic implications of VE/VCO2 in a single-center dyspneic referral cohort (MGH-ExS [Massachusetts General Hospital Exercise Study]) and in a large sample of community-dwelling participants in the FHS (Framingham Heart Study)., Methods: Maximum incremental cardiopulmonary exercise tests were performed. VE/VCO2 was assessed as the slope pre- and post-ventilatory anaerobic threshold (VE/VCO2 pre-VATslope , VE/VCO2 post-VATslope ), the slope throughout exercise (VE/VCO2 overall-slope ), and as the lowest 30-second value (VE/VCO2 nadir )., Results: In the MGH-ExS (N=493, age 56±15 years, 61% women, left ventricular ejection fraction 64±8%), higher VE/VCO2 nadir was associated with lower peak exercise cardiac output and steeper increases in exercise pulmonary capillary wedge pressure (both P <0.0001). VE/VCO2 nadir (hazard ratio, 1.34 per 1-SD unit [95% CI, 1.10-1.62] P =0.003) was associated with future cardiovascular hospitalization/death and outperformed classical VE/VCO2 measures used in heart failure with reduced ejection fraction (VE/VCO2 overall-slope ). In FHS (N=1936, age 54±9 years, 53% women), VE/VCO2 measures taken in low-to-moderate intensity exercise (including VE/VCO2 pre-VATslope , VE/VCO2 nadir ) were directly associated with cardiovascular risk factor burden (smoking, Framingham cardiovascular disease risk score, and lower fitness; all P <0.001)., Conclusions: Impaired ventilatory efficiency is associated with cardiovascular risk in the community and with adverse hemodynamic profiles and future hospitalizations/death in a referral population, highlighting the prognostic importance of easily acquired submaximum exercise ventilatory gas exchange measurements in broad populations with preserved left ventricular systolic function.