Background: With recently gained insights into the pathogenesis of coronary artery restenosis, the genetic control of molecular mechanisms regarding proliferation of smooth muscle cells during neointima formation are receiving increasing attention. The INK4a-Arf locus, through the actions of its product the p16INK4a and p19Arf, is known to regulate the proliferation of various cells. But until recently, its role in the pathogenesis of neointimal hyperplasia has not been definitely documented. In this study, we set out to compare the degree of vascular remodeling and neointima formation in the carotid arteries of the INK4a-Arf deficient mice after cessation of blood flow by arterial ligation. Methods: For the in vitro analysis, the rat SMCs were transfected with vectors containing the siRNA for INK4 sequence. The proliferation of INK4-RNA interference rat SMCs in response to PDGF(10ng/ml) was assessed. For the in vivo experiment, carotid artery ligation was performed in 18 INK4a-Arf +/+ mice, 24 INK4a+/- heterozygous mice, and 18 INK4a-Arf -/- mice. At least 6 animals from each study groups were sacrificed at 7 days, 14 days, and 28 days after ligation. After sacrifice, the arterial specimen obtained were analyzed to determine the intima area, media area, and the intima/media ratio. Result: The INK4 expression as assessed by RT-PCR showed nearly complete inhibition of expression in the INK4-RNA interference rat SMCs. However, the inhibition of INK4 did not result in increased proliferation of SMCs in response to PDGF compared to that of control. In the in vivo experiment, although significant neointima formation was consistently demonstrated for all 3 study groups, the comparison of the average intima area, media area and the intima/media ratio at each time interval did not show any significant difference between the 3 study groups. Conclusion: The results show that p16INK4a and p19Arf may not have a significant role in the pathogenesis of vascular disease such as arterial restenosis. Also, this study demonstrates that the carotid artery neointima proliferation model by carotid artery ligation is a good research model for studying neointimal proliferation and restenosis in mice.