Serum low-density lipoprotein cholesterol concentration is an important regulator of vascular reactivity. This double-blinded study examined the effect of lipid-lowering therapy on myocardial vasodilatory function in young hypercholesterolemic but otherwise healthy men. Fifty-one men (age 35 +/- 4 years) with mild hypercholesterolemia (total cholesterol, 5.6 +/- 0.8 mM ) were randomly assigned to receive pravastatin, 40 mg/day, or placebo for 6 months. Myocardial blood flow was measured at rest and during adenosine-induced hyperemia using positron emission tomography and oxygen-15-labeled water at baseline and after treatment. Pravastatin lowered low-density-lipoprotein cholesterol by 33% from 3.77 +/- 0.76 mM (p < 0.001), whereas placebo had no effect. At baseline, resting and adenosine-induced flow values were 0.85 +/- 0.27 and 3.61 +/- 1.00 ml/min per gram in the pravastatin group and 0.83 +/- 0.18 and 3.17 +/- 0.69 ml/min per gram in the placebo group. Despite significant low-density-lipoprotein cholesterol lowering, resting and adenosine-stimulated blood flow values remained similar at follow-up: 0.86 +/- 0.23 and 3.79 +/- 1.31 vs. 0.78 +/- 0.20 and 3.20 +/- 0.86 ml/min per gram, in the pravastatin and placebo groups, respectively. An improvement in adenosine-induced flow after pravastatin, but not after placebo, was seen only in a subgroup of subjects (n = 15) with relatively low adenosine flow (<4.0 ml/min per gram) at baseline. Six months of cholesterol-lowering therapy with statin treatment has no overall significant effect on coronary vasodilator capacity in healthy subjects with mildly elevated cholesterol levels. A controlled study is needed to further test whether improvement in coronary function is obtained in subjects with initially reduced hyperemic flow response.