The purpose of this study was to determine, using more objective evidence than that reported in previous studies, whether or not exposures to carbon monoxide that produce approximately 2% or 4% blood carboxyhemoglobin levels cause an exacerbation of myocardial ischemia during a progressive exercise test. The objective measurements were based on the development of electrocardiographic evidence of ischemia. In addition, time to onset of angina pectoris was studied. Male subjects, ages 35 to 75, with stable exertional angina pectoris and positive exercise treadmill tests with reproducible ischemic ST-segment changes in their electrocardiograms, were studied. In addition, each subject fulfilled at least one of the following criteria of coronary artery disease: angiographic evidence of at least a 70% occlusion of one or more major coronary artery; prior documented myocardial infarction; or a positive exercise thallium test. Each subject was evaluated on four separate occasions, a qualifying visit and three blinded test visits, which involved exposure (in random order) to air without added carbon monoxide and to air that contained carbon monoxide concentrations calculated to produce approximately 2.2% or 4.4% carboxyhemoglobin, measured by gas chromatography, at the end of the exposure period. These immediate postexposure target levels were set 10% higher than the desired postexercise carboxyhemoglobin levels of 2.0% and 4.0% because exercise while breathing room air results in loss of carbon monoxide. The actual one-minute postexercise levels reached were 2.0% +/- 0.1% (mean +/- standard error of the mean) and 3.9% +/- 0.1%. On each test day, the subject performed a symptom-limited exercise test on a treadmill, was exposed for approximately one hour to air or to one of two levels of carbon monoxide in air, and then performed a second exercise test. Time to the onset of ischemic ST-segment changes and time to the onset of angina were determined for each exercise test. The percent difference for these endpoints on the pre- and postexposure exercise tests was determined, and then the results on the 2%-COHb-target day and the results on the 4%-COHb-target day were compared to those on the control day. Data from the 63 subjects who completed the three test visits and met all protocol criteria were analyzed. There were 5.1% (p = 0.01) and 12.1% (p less than or equal to 0.0001) (trimmed mean) decreases in the time to development of ischemic ST-segment changes after the 2%- and 4%-COHb-target exposures, respectively, compared to the control day.(ABSTRACT TRUNCATED AT 400 WORDS)