Different components of the renin-angiotensin system (RAS) have been demonstrated in atherosclerotic plaques. However, the involvement of the RAS in the complex process of in-stent restenosis is not yet clear. In this prospective, randomized, double-blind, controlled proof-of-concept study, we compared the 2 different pharmacological approaches, selective AT(1)-receptor-blockade with candesartan vs ACE inhibition with quinapril to reduce in-stent restenosis after stent angioplasty of the superficial femoral artery. Twenty-two hypertensive patients with stage IIb peripheral occlusive arterial disease and severe claudication who had been successfully treated with percutaneous transluminal angioplasty (PTA) and stent implantation were randomly assigned to receive daily doses of either candesartan (32 mg) or quinapril (20 mg). Primary end point was restenosis 6 months after intervention, assessed by angiography. Secondary end points were pain-free walking distance, determined by treadmill ergometry; determination of crurobrachial indices; and intima-media thickness (IMT). At 6 months, the rate of restenosis on angiography was 34% in the candesartan group and 71% in the quinapril group (P = .043). Relevant restenosis was found in 3 patients (27%) in the candesartan group and in 7 patients (64%) in the quinapril group. Patients in the candesartan group were able to walk farther on a treadmill (increase: 135 m +/- 20 m) compared with patients in the quinapril group (increase: 83 m +/- 21 m). The IMT at the stent edge was not significantly different in the 2 groups (candesartan: 1.9 mm +/- 0.5 mm; quinapril: 2.0 mm +/- 0.3 mm). This study revealed significant benefit of a pharmacological restenosis regimen using the AT(1)-receptor antagonist candesartan in patients with severe atherosclerosis after superficial femoral artery stenting compared with treatment with the ACE inhibitor quinapril. Further prospective studies in patients are required to confirm these results.