The acute changes in coronary blood flow and coronary resistance that occur in response to cigarette smoking have not been accurately determined. To define the factors that affect this response, coronary sinus blood flow was measured in 16 patients (group I) with coronary artery disease and in 6 patients (group II) without angiographically detectable coronary disease. Seven patients (group IA) had severe (greater than or equal to 75%) proximal left coronary lesions and nine patients (group IB) had significant distal lesions with 50% or less proximal stenoses. Group I had a smaller overall increase (increases 1.6 +/- 5.3%) in coronary sinus blood flow than did group II (increases 7.7 +/- 6.1%) (p less than 0.05). Coronary resistance increased overall (increases 2.7 +/- 5.3%) in group I but decreased (decreases 2.4 +/- 3.4%) in group II (p less than 0.05). Patients in group IA had a highly significant increase in coronary resistance as compared with group IB (increases 7.0 +/- 4.2% versus decreases 0.9 +/- 2.6%) (p less than 0.001). Coronary sinus flow tended to decrease (decreases 1.2 +/- 4.6%) in group IA but to increase (increases 3.8 +/- 5.1%) in group IB (p = 0.06). It is concluded that smoking increases coronary resistance in patients with coronary artery disease. A greater impact is observed in patients with a severe proximal stenosis than in those with a distal stenosis. It is proposed that smoking increases coronary artery tone at the site of the stenosis, limiting the coronary flow response proportionally to the size of the affected vascular bed.