BACKGROUND Cigarette smoking is a major preventable risk factor for coronary artery disease and sudden cardiac death. However, the effect of acute and long-term cigarette smoking on coronary vasodilatory capacity and myocardial flow reserve has not been quantified in humans. RESULTS To examine the effect of short-term and long-term smoking, myocardial blood flow was quantified at rest and during dipyridamole-induced hyperemia (0.56 mg/kg) in 12 smokers (10 males and 2 females; mean age, 27 +/- 4 years) under baseline conditions (reflecting the effect of long-term smoking) and during short-term cigarette smoking with 13N ammonia, positron emission tomography, and a two-compartment model. Twelve sex- and age-matched nonsmokers served as control subjects. Smoking significantly increased the rate-pressure product at rest from 7525 +/- 1290 to 9160 +/- 1125 (P < .001 versus baseline), which was paralleled by a proportional increase in myocardial blood flow at rest (0.70 +/- 0.17 versus 0.88 +/- 0.17 mL.g-1.min-1; P < .05 versus baseline). In contrast, hyperemic blood flow declined from 2.23 +/- 0.35 at baseline (P = NS versus control) to 1.98 +/- 0.32 mL.g-1.min-1 during smoking (P < .01 versus baseline). Accordingly, the myocardial flow reserve declined from 3.36 +/- 0.83 in smokers at baseline to only 2.28 +/- 0.28 during smoking (P < .0001 versus baseline). Thus, myocardial blood flow and flow reserve were similar in young, long-term smokers and young, healthy nonsmokers. CONCLUSIONS Short-term smoking increases the coronary vasomotor tone during dipyridamole-induced hyperemia and markedly reduces the myocardial flow reserve. In contrast, long-term smoking does not attenuate the coronary vasodilatory capacity in young individuals with a relatively short smoking history. It might be speculated that the short-term reduction in the coronary vasodilatory capacity during smoking could lower the ischemic threshold in smokers with coronary artery disease and contribute to the increased risk for sudden cardiac death.