Background and Purpose-The pathophysiology of vascular lesions after balloon angioplasty remains poorly understood.A major limitation of most experimental studies in this regard is that injury was assessed in healthy arteries. Our aim was to study the effects of hypercholesterolemia in a mouse vascular injury model that mimics human balloon angioplasty. Methods-Carotid balloon distension was performed in wild-type (WT) mice on a normal diet (ND), in apolipoprotein E-deficient (ApoE Ϫ/Ϫ ) mice on ND and in ApoE Ϫ/Ϫ mice fed a high cholesterol diet (CD). Results-Medial cell death (TUNEL) was elevated in all mice at 1 hour and 1 day after angioplasty without differences between the groups. We found enhanced intimal inflammation (%CD45-positive cells) and vascular cell adhesion molecule-1 expression at 7 days (PϽ0.05; nՆ4) as well as increased proliferation rates (BrdU-index) in ApoE Ϫ/Ϫ CD at 7 and 28 days postinjury (PϽ0.05; nՆ5). Four weeks after injury, these events led to enhanced neointima in ApoE