Electronic nicotine delivery systems, often referred to as e-cigarettes, are popular tobacco products frequently advertised as safer alternatives to traditional cigarettes despite preliminary data suggesting a potential negative cardiovascular impact. Cardiorespiratory fitness is a critical cardiovascular health marker that is diminished in individuals who consume traditional tobacco products. Whether the use of e-cigarettes impacts cardiorespiratory fitness is currently unknown. Thus, the purpose of this study was to investigate the impact of regular e-cigarette use on cardiorespiratory fitness in young healthy adults. Twenty-six users of e-cigarettes (ECU, 13 males, and 13 females; age: 24 ± 3 yr; e-cigarette usage 4 ± 2 yr) and 16 demographically matched nonusers (NU, 6 males, and 10 females; age: 23 ± 3 yr) participated in this study. Cardiorespiratory fitness was measured by peak oxygen consumption (V̇o) during a cardiopulmonary exercise test. Measurements of chronotropic response, hemodynamic, oxygen extraction, and utilization were also evaluated. Our results suggest that regular users of e-cigarettes exhibited significantly lower peak oxygen consumption when compared with nonusers, even when controlled by fat-free mass and lean body mass. Hemodynamic changes were not different between both groups during exercise, whereas lower chronotropic responses and skeletal muscle oxygen utilization were observed in users of e-cigarettes. Results from the present study demonstrate that young, apparently healthy, regular users of e-cigarettes exhibit significantly reduced cardiorespiratory fitness, lower chronotropic response, and impaired skeletal muscle oxygen utilization during exercise. Overall, our findings contribute to the growing body of evidence that supports adverse effects of regular e-cigarette use on cardiovascular health. E-cigarettes are tobacco products frequently used by youth and young adults. Little is known about the long-term health effects of their prolonged use. Results from the present study demonstrate that young, apparently healthy, regular users of e-cigarettes exhibit significantly reduced cardiorespiratory fitness, a marker of cardiovascular health and a predictor of all-cause mortality. We also identified that the young users of e-cigarettes present with lower chronotropic response and impaired skeletal muscle oxygen utilization during exercise.