Objective: Tetramethylpyrazine, a drug originally isolated from the rhizome of Ligusticum walliichi, is an inhibitor of phosphodiesterase and inhibits platelet aggregation and smooth muscle cell proliferation. The effect of the tetramethylpyrazine-eluting stent (TES) on preventing in-stent restenosis was investigated in comparison with control bare metal stents in a porcine coronary stent restenosis model. Methods: The TES was prepared by spray-coating the 2.5 to 3.0mm×15 to 20mm bare metal stents with Tetramethylpyrazine monomer, methyl methacrylate copolymer, and polyglycolic acid. Stent overdilation injury (stent:artery=1.1 to 1.2:1.0) was made with control bare stents (n=5) and TES (n=5) in porcine coronary arteries. Follow-up quantitative coronary angiography (QCA) and histopathological assessments of stented coronary arteries were performed 4 weeks after stenting. Results: Quantitative coronary angiography showed the late lumen loss (0.28±0.08mm versus 1.70±0.52mm; P=0.004) and percentage diameter stenosis (10.0±2.1% versus 60.2±23.5%; P=0.01) were significantly lower in the TES group than that in the control group. Histopathological assessments of stented coronary arteries showed that the injury score and the in-stent area were similar between the groups (P＞0.05), whereas the lumen area was significantly larger (4.34±0.93 mm2 versus 1.29±1.02mm2; P=0.011) in the TES group than that in the control group. The number of proliferating cell nuclear antigen-positive cells was also significantly decreased in the TES group compared with the control group (14.7±2.5% versus 23.6±3.2%; P=0.008). Moreover, apoptosis was enhanced in TES group while regrowth of endothelium was similar between the groups. Conclusions: TES inhibited the neointimal hyperplasia and reduced in-stent restenosis in a porcine coronary artery restenosis model.