Increased vascular constriction has been observed at the site of atherosclerotic lesions, suggesting an association between atherosclerosis and altered vascular tone. While atherosclerosis may increase sensitivity to exogenous vasoconstrictors, little is known about the response of normal and atherosclerotic coronary arteries to an exogenous stimulus that excites the sympathetic nervous system. Therefore, we studied the response to cold pressor test (CPT) using quantitative angiography and Doppler flow velocity measurements in eight patients with angiographically normal coronary arteries (group I), nine patients with mild coronary atherosclerosis (< 50% diameter narrowing) (group II), and 13 patients with advanced coronary stenoses (> 50% diameter narrowing) (group III). In 31 segments of angiographically smooth arteries in group I, the CPT produced vasodilation from a control mean diameter of 2.68 ± 0.09 (mean ± SE) to 2.99 ± 0.09 mm at peak CPT (p < 0.001), a 12 ± 1 % increase in diameter. In group II, 27 irregular segments constricted to peak CPT from a mean control diameter of 1.82 ± 0.12 to 1.66 ± 0.12mm (p< .001), a 9 ± 1%decrease, while 10 smooth segments dilated from a mean control diameter of 1.98 ± 0.11 mm to 2.34 ± 0.15 mm (p < .01), a 19 ± 2% increase in diameter. Likewise, in group III, the 17 stenotic segments constricted from 1.16 ± 0.09 to 0.89 ± 0.09 mm (p < .001), a 24 ± 6% decrease; the irregular segments also constricted from 2.44 ± 0.11 to 2.22 ± 0.12 mm (p = .002), a 10 ± 2% decrease. In contrast, two smooth segments dilated from 2.98 to 3.23 mm (mean), an 8% increase in diameter. Coronary blood flow increased 65 ± 4% (mean) during CPT in group I, it increased 15 ± 6% in group II, and it decreased 39 ± 8% in group III. The vasodilator response in four normal patients was partly inhibited by the administration of intracoronary propranolol (17 ± 3% increase during control, 10 ± 2% increase after propranolol, 41% less dilation; p = .002). We conclude that the response of normal coronary arteries to the CPT test is dilation, in part related to β-adrenoreceptor stimulation and possibly flow-mediated endothelial dilation or α2-adrenergic activity. The paradoxical vasoconstrictor response induced by atherosclerosis may represent altered catecholamine sensitivity and/or a defect in endothelial vasodilator function. The presence of atherosclerosis impairs vasodilator responses and thus may contribute to the pathogenesis of myocardial ischemia.