The effect of breathing 100 ppm of carbon monoxide versus compressed, purified air for 1 h on maximal treadmill exercise was studied (double-blind crossover design) in 10 middle-aged, healthy nonsmokers. The mean venous carboxyhemoglobin level significantly increased from 1.67% to 3.95% after breathing carbon monoxide (P < 0.001) and significantly decreased from 1.63% to 1.30% after breathing compressed, purified air (P < 0.001). The mean exercise time until exhaustion significantly decreased from 697.7 s to 662.7 s after breathing carbon monoxide (P < 0.001) and insignificantly increased from 694.9 s to 703.4 s after breathing compressed, purified air. Ischemic S-T segment depression ≥ 1.0 mm after exercise occurred in 1 of 10 subjects after exercise following carbon monoxide inhalation. Increased carboxyhemoglobin levels of the magnitude encountered after smoking or heavy atmospheric pollution impair exercise performance in normal persons.