Previous studies suggested that cigarette smoking 1) inhibits an increase in coronary blood flow that should occur with increased myocardial oxygen demands, and 2) alters thromboxane and prostacyclin production, causing vasoconstriction and platelet aggregation. In 38 smokers (26 men and 12 women, aged 50 ± 8 years [mean ± standard deviation]) with coronary artery disease, systemic and coronary hemodynamic and serologic variables were measured before and after smoking two cigarettes (in 8 to 10 minutes) (21 patients) or 8 to 10 minutes without smoking (17 patients; control group). No variable changed in the control group. Smoking increased (p < 0.05) heart rate-systolic pressure product, cardiac output and maximal first derivative of left ventricular pressure (dP/dt) without significantly changing the coronary sinus concentrations of thromboxane B2 or 6-keto-prostaglandin F1α (the stable metabolites of thromboxane A2 and prostacyclin, respectively). Smoking did not increase coronary flow in 6 of 11 patients with greater than 70% stenosis of the proximal left anterior descending or circumflex coronary artery, or both, whereas it caused an increase in coronary flow in all 10 patients without proximal stenoses (p = 0.006). To determine if smoking altered the response of coronary flow to increased myocardial oxygen demands, 10 smokers (5 men and 5 women, aged 48 ± 9 years) underwent atrial pacing for 5 minutes followed 15 minutes later by atrial pacing for 5 minutes during smoking. In the five patients without proximal left coronary artery stenoses, coronary flow increased 26 ± 29 ml/min with pacing and 45 ± 21 ml/min with pacing/smoking (p = 0.018). In contrast, in the five patients with proximal stenoses, coronary flow increased 39 ± 24 ml/min with pacing, but only 36 ± 16 ml/min with pacing/smoking (p = NS). Thus, in smokers with coronary artery disease, smoking increases myocardial oxygen demands. However, in some individuals with severe proximal stenoses of the left coronary artery, it may induce no change or cause a decrease in coronary blood flow. The net effect of smoking on coronary blood flow appears to be influenced by the location and severity of atherosclerotic coronary artery disease.