BACKGROUND Initial concerns about the coronary side-effect potential of the anti-migraine drug sumatriptan and second-generation triptans initiated cranioselectivity studies using proximal human coronary arteries. However, myocardial ischaemia may originate from both large and small human coronary arteries. METHODS We investigated the contractions to sumatriptan in proximal (internal diameter 2-3 mm), distal (internal diameter 1,000-1,500 μm) and small (internal diameter 500-1,000 μm) human epicardial coronary arteries and compared these with contractions in the human middle meningeal artery. Concentration response curves to sumatriptan in human coronary arteries were constructed in the absence or presence of the 5-hydroxytryptamine1B (5-HT1B) receptor antagonist SB224289 and the 5-HT1D receptor antagonist BRL15572. The effect of sumatriptan on increased cyclic adenosine monophosphate (cAMP) levels induced by forskolin in proximal and distal coronary artery segments was investigated using a biochemical assay. Western blotting was used to analyse the 5-HT1B receptor density in the human arteries. RESULTS Contractions in the proximal human coronary artery were significantly smaller than those in the human meningeal artery, as we showed previously. In contrast, contractions to sumatriptan in distal and small human coronary arteries were not different from those in the human meningeal artery. The 5-HT1B receptor antagonist SB224289, but not the 5-HT1D receptor antagonist BRL15572, inhibited the contraction induced by sumatriptan in the coronary arteries. Moreover, in distal, but not in proximal, coronary arteries, sumatriptan inhibited the increase in cAMP levels induced by forskolin. Contrary to our expectations, the 5-HT1B receptor expression was more pronounced in the proximal human coronary artery than in the distal and small human coronary artery. CONCLUSIONS Based on functional experiments in distal and small human coronary arteries, contractions to sumatriptan are not as cranioselective as previously assumed. However, the vast clinical experience with sumatriptan and other triptans has proven that these drugs are cardiovascularly safe when contraindications are taken into account.