Abstract: AIM: To investigate the role of p38 mitogen-activated protein kinase (MAPK) in oxidative stress response to intimal lesion induced by rabbit carotid adventitial injury. METHODS: A model of intimal lesion induced by rabbit carotid adventitial injury was set up with collagenase digestion and mechanical dissection in hypercholesterolemic rabbits. Blood biochemical tests ［total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C)］, neointimal area (NIA), production of reactive oxygen species (ROS) and expression and location of phospho-p38 MAPK were analyzed at different time points after carotid adventitial injury in both control group and atorvastatin group. RESULTS: ROS production and p38 MAPK activation were observed at 1 day after carotid adventitial injury and remained elevated for at least 28 days. Long-term treatment (4 weeks) with HMG-CoA reductase inhibitor atorvastain reduced the vascular response to carotid adventitial injury in hypercholesterolemic rabbits, decreased TC and LDL-C, and alleviated intimal hyperplasia compared with those in control group (P<0.05). CONCLUSION: Increased production of ROS and the sustained activation of p38 MAPK play an important role in the formation of neointima induced by carotid adventitial injury.