Disturbed vasomotor function in coronary arteries has clinical importance in early stages of coronary artery disease (CAD), as it may contribute to the potential risk for an ischaemic coronary event. In the present study, we have investigated the relationship between coronary vasomotor function and the extent of CAD. The response to acetylcholine and nitrate infusion was assessed by quantitative coronary angiography. The extent of CAD was categorized into two groups: minor CAD (normal coronary arteries and vessel wall irregularities) and significant CAD (one-, two- and three-vessel disease). A total of 277 patients with stable angina pectoris, referred for a first diagnostic coronary angiography, were eligible for analysis (mean age 57 years, 61% male). The response to nitrate was significantly impaired in patients with significant CAD ( P <0.001). On the other hand, the response to acetylcholine was not different between the two groups ( P =0.12); however, a trend between the response to acetylcholine and the extent of CAD was observed in patients without a previous infarction ( P =0.07), which was a significant interaction variable. Furthermore, a significant relationship between coronary vasomotor response and the number of cardiovascular risk factors was observed ( P <0.05). In conclusion, in a heterogeneous group of patients, coronary vasomotor function measured by nitrate infusion was more strongly associated with the extent of CAD and the number of risk factors than the response to acetylcholine. These data suggest that, in patients with advanced atherosclerosis or multiple risk factors, the vasomotor dysfunction is not solely restricted to the endothelium.