OBJECTIVE: To observe the effect of simvastatin on the expression of high mobility group box-1 protein (HMGB1) and morphology of atherosclerotic plaques in atherosclerotic rats, to ascertain whether HMGB1 plays a role in the preventive mechanism of simvastatin from atherosclerosis (AS). METHODS: Sixty Wistar rats were divided randomly into three groups: control group, model group and simvastatin treatment group. Gastric gavage of vitamin D3 with high fat food was used to reproduce atherosclerotic rat model. The rats in the treatment group were treated with simvastatin of 2.5 mg x kg(-1) x d(-1) (gastric perfusion) 8 weeks after fat diet. The expression of the histopathology and protein of HMGB1 in atherosclerotic plaques of the aorta was observed by immunohistochemistry at 10 weeks and 12 weeks. The gene expression of HMGB1 at atherosclerotic plaques of aorta was observed with real time-polymerase chain reaction (RT-PCR). The morphology of the atherosclerotic plaques was observed. RESULTS: The expression of HMGB1 increased significantly in atherosclerotic plaques in model group, and simvastatin could evidently inhibit the expression of HMGB1, and it was more obvious in 12-week group. Compared with control group, the HMGB1 mRNA expression was upregulated in all atherosclerotic model groups (10 weeks: 19.695+/- 1.418 vs. 2.981+/-0.753, 12 weeks: 20.542+/-1.132 vs. 3.219+/-0.332, both P<0.01). In the simvastatin treatment group, the gene expression of HMGB1 was lower than the age-match model group at 10 weeks (15.798+/-0.891) and 12 weeks (12.641+/-0.734), and in the 12-week treatment group it was lower than that in the 10-week treatment group (P<0.05 or P<0.01). In the model group, the ring-shape calcified atherosclerotic plaques were extensively found in the wall of the aorta. Simvastatin could obviously inhibit the formation of the atherosclerotic plaques, and the effect was more obvious in the 12-week treatment group than that of the 10-week treatment group. CONCLUSION: Simvastatin can alleviate the formation of the atherosclerotic plaques in the atherosclerotic rats, decrease the protein and mRNA expression of HMGB1. The results suggest that the vessels are protected from forming AS through alleviating inflammatory reaction.