Coronary flow reserve is mainly influenced by the combination of luminal stenosis and vascular dilation capacity. Thus, after statin treatment, the reduction of ischemic threshold in patients submitted to exercise testing could be intensely influenced by angiographic severity. In this study, we verify the effect of statin treatment on exercise-induced myocardial ischemia in hypercholesterolemic patients with a broad range of coronary angiographic severities. Patients with 2 consecutive positive exercise tests, coronary stenosis > or =70%, total cholesterol > or =300 mg/dl, and triglycerides < or =200 mg/dl were randomly assigned to a 16-week treatment period with either diet alone (n = 39) or diet plus statins (simavastatin, n = 31 and pravastatin, n = 10). Statin-treated patients had a significant variation in total cholesterol (-46% vs -2.7%; p <0.01), low-density lipoprotein cholesterol (-58% vs 0.8%; p <0.01), and high-density cholesterol (+28% vs -6%; p <0.05) in comparison with the diet-only group. After 16 weeks of treatment, 36 patients (92%) in the diet group still had positive exercise tests, whereas only 7 patients (15%) of the statin group had a positive test (p <0.01). The proportion of positive tests was significantly reduced in subgroups of patients with 1-, 2-, or 3-vessel disease. Regarding the severity of coronary stenosis, the proportion of positive tests was significantly reduced in patients with stenosis between 70% and 90% and in patients with stenosis > or =90%. Moreover, the proportion of positive tests tended to decrease to a greater extent in patients with mild coronary disease. In conclusion, cholesterol-lowering treatment with statins reduces exercise-induced myocardial ischemia in hypercholesterolemic patients with mild or severe epicardial coronary stenosis.