To study whether vascular dysfunction in hypercholesterolaemia is reversible, we investigated patients without overt arterial disease who were taking maintenance treatment for hypercholesterolaemia. Medication was stopped for 2 weeks, reinstituted for 12 weeks, and again stopped for 6 weeks. During both maintenance treatment and the 12 weeks of step-up medication the lipid profile was improved but did not return to normal. Dose-response curves for serotonin-induced vasodilatation, an index of nitric oxide-dependent vasodilatation, showed a comparable and significant rightward shift after a medication-free period of 2 and 6 weeks compared with control subjects, indicating endothelial dysfunction, which was already maximum after 2 weeks. After 12 weeks of lipid-lowering medication, the difference in endothelial function between controls and patients had disappeared. Co-infusion of L-arginine, the substrate for nitric oxide synthase, returned the impaired serotonin response during hypercholesterolaemia to normal, but had no effect on this response in controls or in patients while on lipid-lowering medication. Neither endothelium-independent vasorelaxation, assessed by sodium nitroprusside infusion, nor vasoconstriction induced by the nitric oxide blocker L-NMMA, were different between controls and patients, whether the latter were on or off lipid-lowering medication. Our results show an L-arginine-sensitive, impaired nitric-oxide-mediated vascular relaxation of forearm resistance vessels in hypercholesterolaemia which is reproducible, and reversible after short-term lipid-lowering therapy. Demonstration of such changes in this readily accessible vascular bed will allow larger trials assessing vascular function during lipid-lowering therapy to be done.