<b><i>Background:</i></b> Obese men show higher O₂ consumption than lean men during physical exercise, with a trend toward higher peripheral O₂ extraction; this is probably due to their larger muscle mass. <b><i>Objectives:</i></b> The aim of this study was to examine this phenomenon by measuring 2 vasoactive substances, endothelin-1 (ET-1) and nitric oxide (NO), during a progressive submaximal exercise. <b><i>Methods:</i></b> Seventeen obese (body mass index [BMI] 38.6) and 15 lean (BMI 22.5) men performed a maximal progressive cycle ergometer exercise to determine peak power output (PPO) and peak O₂ consumption (<i>V</i><b>∙</b><i>O</i>₂_<i>peak</i>); thereafter, they performed a submaximal cycle ergometer incremental test (every 6 min) at the same percentage of <i>V</i><b>∙</b><i>O</i>₂_<i>peak</i> until they reached 57.5% PPO. Blood samples were collected at rest and at the end of every step to measure ET-1 and NO concentrations. <b><i>Results:</i></b> At rest, the ET-1 and NO concentrations in obese men and lean controls were the same. However, during exercise, the ET-1 concentration at each step was significantly lower (<i>p</i> < 0.05) in the obese group. There was no significant difference in NO concentration between the 2 groups, although the increase at the beginning of the exercise session was faster in obese individuals. During submaximal exercise, end-tidal O₂ pressure (PETO₂) was lower in the obese group, with a significant difference in the PETO₂/fat-free mass ratio at each step. <b><i>Conclusions:</i></b> ET-1 and NO levels during physical exercise are different in obese versus lean men. This may support the notion that increased O₂ consumption in obesity is due to different behaviors of the cardiorespiratory and circulatory systems.