Background: 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. Objectives: 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. Methods: 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 (V[BULLET OPERATOR]O2peak); thereafter, they performed a submaximal cycle ergometer incremental test (every 6 min) at the same percentage of V[BULLET OPERATOR]O2peak 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. Results: 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 (p < 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. Conclusions: 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.