Background and Aims: Nicotine is a major component of cigarette smoke and has been found to play an important role in angiogenesis. However, whether nicotine plays a role in restenosis has not been determined. Therefore, the aim of the present study was to determine the effects of nicotine on angiogenesis and restenosis in a rabbit model. Methods: Forty male New Zealand White rabbits were randomly divided into control and low-, middle-, and high-dose (0.005, 0.05 or 5 µg/kg, respectively) nicotine-treated groups. Balloon catheter denuding injury iliac artery and ligation of left anterior descending coronary artery were performed in all animals fed with a high-cholesterol diet (HCD) beginning 2 weeks before operation. Nicotine was administered daily by intramuscular injection in the ischemic hindlimb for 3 weeks. Control rabbits received an equal volume of phosphate-buffered saline alone. Collateral vessels of the ischemic hindlimb were observed by angiography of abdominal aorta, and the density of intramyocardial microvessels and proliferative activity of balloon-injured arteries were examined by immunohistochemistry. Serum levels of lipids and the indexes of hepatic or renal functions were also determined before HCD and after nicotine treatment. Results: One rabbit in control, two in low-, one in middle- and two in high-dose groups died during the experiment. The remaining 34 rabbits were included in the study. Two or five weeks after HCD, the levels of serum lipids were significantly increased in all groups, but there was no significant difference of the levels between control and nicotine-treated groups 3 weeks after treatment; the indexes of hepatic or renal functions showed no significant changes 3 weeks after nicotine treatment; there were no significant differences on collateral vessels shown by angiography in all four groups; the density of intramyocardial microvessels in three nicotine-treated groups was significantly higher than that in control group; but the intimal area and proliferative activity in the balloon-injured arteries in three nicotine-treated groups were also higher than those in control group. Conclusions: The present study shows that intramuscular administration of nicotine for 3 weeks could not increase arteriogenesis in ischemic hindlimb of rabbits, but is capable of significantly promoting intramyocardial angiogenesis. Nicotine can also accelerate intimal proliferation and thickening of balloon catheter denuding injury iliac artery, so it may contribute to the development of restenosis.