Cigarette smoking is one of the main predisposing factors for atherosclerosis, which can lead to vascular inflammation. Emerging research has demonstrated that the rate of restenosis is increased following angioplasty in smokers. Sophocarpine, one of the Sophora alkaloids, can play the antiinflammatory role in cells. This study aimed to assess whether sophocarpine can alleviate the restenosis induced by cigarette smoke in rats post-angioplasty. Fifteen male Sprague-Dawley rats were randomized into three groups (control group, smoking group, smoking and injected with sophocarpine group). An established balloon-induced carotid artery injury was performed to all the groups. For the balloon-injured carotid arteries, Verhoeff-Van Gieson stain was used to detect the area of neointima and media. Then the ratio of neointima to media (I/M ratio) was calculated. For the contralateral carotid arteries, the level of MAP kinase kinase 3 (MKK3), MAP kinase kinase 6 (MKK6), Phospho-MKK3/6, p38, Phospho-p38, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were measured. The I/M ratio of smoking group is larger than that of control group. However, sophocarpine could dramatically reduce the I/M ratio compared to smoking group. Cigarette smoke could induce the expression of Phospho-MKK3/6, Phospho-p38, IL-1β and TNF-α, and treatment with sophocarpine could inhibit such effects. The levels of MKK3, MKK6 and p38 were not under the influence of cigarette smoke or sophocarpine. Sophocarpine could alleviate the cigarette smoke-induced restenosis in rat carotid arteries after balloon injury and the mechanism of its protective effect might be the inhibition of the inflammatory reaction. This also implies sophocarpine has the potential therapeutic applicability in preventing restenosis after angioplasty in smokers.