Patients with atherosclerotic cardiovascular disease may be adversely affected by the presence of carboxyhemoglobin, even at low concentrations. We investigated the effects of carbon monoxide exposure on myocardial ischemia during exercise in 63 men with documented coronary artery disease. On each test day, subjects performed two symptom-limited incremental exercise tests on a treadmill; the tests were separated by a recovery period and 50 to 70 minutes of exposure to either room air or air containing one of two concentrations of carbon monoxide (117 +/- 4.4 ppm or 253 +/- 6.1 ppm). The order of exposure was assigned randomly. On each occasion, neither the subjects nor the study personnel knew whether the subjects had been exposed to room air or to one of the concentrations of carbon monoxide. Exposure to room air resulted in a mean carboxyhemoglobin level of 0.6 percent, exposure to the lower level of carbon monoxide resulted in a carboxyhemoglobin level of 2.0 percent, and exposure to the higher level of carbon monoxide resulted in a level of 3.9 percent. An effect of carbon monoxide on myocardial ischemia was demonstrated objectively by electrocardiographic changes during exercise. We observed a decrease of 5.1 percent (90 percent confidence interval, 1.5 to 8.7 percent; P = 0.02) and a decrease of 12.1 percent (90 percent confidence interval, 9.0 to 15.3 percent; P less than or equal to 0.0001) in the length of time to a threshold ischemic ST-segment change (ST end point) after carbon monoxide exposures that produced carboxyhemoglobin levels of 2.0 percent and 3.9 percent, respectively. The length of time to the onset of angina decreased by 4.2 percent (90 percent confidence interval, 0.7 to 7.9 percent; P = 0.054) at the 2.0 percent carboxyhemoglobin level and by 7.1 percent (90 percent confidence interval, 3.1 to 10.9 percent; P = 0.004) at the 3.9 percent carboxyhemoglobin level. Significant dose-response relations were found in both the change in the length of time to the ST end point (P less than or equal to 0.0001) and the change in the length of time to the onset of angina (P = 0.02). We conclude that low levels of carboxyhemoglobin exacerbate myocardial ischemia during graded exercise in subjects with coronary artery disease.