Environmental exposure to inhaled carbon monoxide (CO) increases coronary artery disease risk. Sudden cardiac death, a frequent manifestation of coronary artery disease, is usually a result of ventricular dysrhythmia. The effect of exposure to CO at sea level (CO/SL) and simulated high (2.1 km) altitudes (CO/HA) on the incidence of cardiac ectopy in subjects with coronary artery disease was investigated. A double-blind crossover study was conducted, with random-order assignment, and each subject served as his own control. Seventeen men with documented coronary artery disease and stable angina pectoris performed cardiopulmonary exercise stress tests after random exposure to either CO or clean air (CA) at sea level (CA/SL) or at a simulated 2.1-km high altitude (CA/HA). The individual CO and HA exposure conditions were each selected to reduce the percentage of oxygen saturation of the subjects' arterial blood by 4%. Subjects' blood carboxyhemoglobin levels were increased from an average of 0.62% after clean-air exposure to 3.91% of saturation after CO exposure. The percentage of oxygen saturation in arterial blood was reduced from a baseline level of 98% to approximately 94% after CO/SL or CA/HA and to approximately 90% after CO/HA. Compared with the CA/SL (i.e., 10 premature ventricular contractions [PVCs]), the average incidence of exercise-induced ventricular ectopy was approximately doubled after all exposures (CO/SL = 18 PVCs, CA/HA = 16 PVCs, and CO/HA = 19 PVCs), and a significant trend (p < .05) of increased ectopy with decreased oxygen saturation in arterial blood was observed. Yet, among subjects who were free from ectopy (n = 11) on CA/SL, only 2 subjects developed ectopy after CO/HA. No episodes of ventricular tachycardia or fibrillation occurred. The findings indicated that exposure to increased levels of hypoxemia, resulting from hypoxic and/or CO exposures, increased the susceptibility to ventricular ectopy during exercise in individuals with stable angina pectoris; however, this risk was nominal for those without ectopy.