Elevated blood cholesterol is a major risk factor for atherosclerosis. Recent studies show that lowering cholesterol reduces the risk of vascular disease, but the precise mechanisms for vascular improvement are not fully understood. Furthermore, it is not known whether the beneficial effects of cholesterol lowering extend to the skin microvasculature. In this unrandomized, open design study, we used iontophoresis and laser Doppler flowmetry to examine forearm skin perfusion in hypercholesterolaemic patients with PAOD before and after cholesterol-lowering therapy with fluvastatin. Endothelium-dependent and -independent vasodilatation were measured following skin iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP), respectively. Before cholesterol-lowering, vascular responses to ACh and SNP were reduced significantly in patients compared with responses in control subjects (p <0.001 and p <0.05, ANOVA, respectively). Fluvastatin therapy (40 mg/day) for 24 weeks significantly reduced total cholesterol (7.3+/-0.3 to 6.0+/-0.2 mmol/l, p <0.001) and LDL cholesterol (5.4+/-0.5 to 4.2+/-0.4 mmol/l, p <0.01). Vasodilatation to SNP was significantly improved at week 24 (p <0.05). In patients with hypercholesterolaemia and PAOD, cholesterol-lowering with statin therapy significantly improved endothelium-independent vascular responses to SNP in skin microvessels. The application of the non-invasive techniques of iontophoresis and laser Doppler flowmetry may provide useful markers for the assessment of microvascular function in this group of patients.