To investigate the action of calcitonin gene-related peptide (CGRP) on human epicardial coronary arteries, six patients received intracoronary CGRP at doses of 50, 100, and 200 ng/min. The effect of CGRP was measured angiographically with a computerized analysis system. A dose-dependent increase in coronary arterial diameter was observed. At the highest dose there were 34%, 7%, 38%, and 40% mean increases in the diameters of the circumflex, proximal, mid, and distal left anterior descending arteries, respectively. No further increase in diameter was found after a subsequent dose of 1 mg intracoronary isosorbide dinitrate. Prior infusion of CGRP did not prevent coronary arterial spasm induced by ergonovine in two patients with variant angina, but a subsequent bolus of CGRP partially relieved the spasm. We propose that CGRP has a role in the regulation of coronary vascular smooth muscle tone.