Background: Platelet-derived peptide and nonpeptide growth factors are known to play pivotal roles in neointimal proliferation. Along with its antiplatelet activity of reducing P-selectin and hs-CRP, clopidogrel has also been shown to have anti-inflammatory properties. The aim of this study is to find out by modulating inflammation if clopidogrel can affect neointima formation in balloon-denuded iliac arteries of hypercholesterolemic rabbits. Methods and Results: Rabbits were fed with 1% cholesterol diet with (n = 20) or without (n = 20) clopidogrel (10 mg/kg body weight) for 7 days followed by balloon-denudation of endothelial layer in both the iliac arteries and continued on 0.15% cholesterol diet with or without clopidogrel. Four weeks later, the denuded area in both iliac arteries was radiated (n = 11, cholesterol-only group; n = 9, clopidogrel group) or sham treated (n = 10 from each group). Four weeks after radiation, animals were sacrificed and arterial segments were processed for morphometry. In the sham-treated clopidogrel group, neointimal area, percent stenosis, and macrophage score were 39% (P = 0.01), 32% (P = 0.02), and 50% (P = 0.02) smaller, respectively, when compared to the cholesterol-only group (0.48 ± 0.18, 32.42 ± 13.04, and 1.5 ± 0.83). There were no differences in the radiated group (0.89 ± 0.32, 50.34 ± 13.00, and 1.88 ± 1.27 vs. 0.93 ± 0.38, 59.41 ± 11.41, and 2.00 ± 0.74, respectively). Conclusion: This study demonstrates that clopidogrel reduces inflammation and neointimal formation in balloon-denuded iliac arteries of hypercholesterolemic rabbits.