Smoking is a leading cause of flap failure. Varenicline-assisted smoking cessation has shown beneficial effects on vascular endothelial function. The aim of this study was to determine whether varenicline conveys beneficial effects for skin flap survival. Twenty-four rats were randomly divided into four groups of six. The rats in the control group received normal saline subcutaneous injections, and those in the nicotine group received subcutaneous nicotine injections. The rats in the varenicline group received varenicline intraperitoneally, and those in the nicotine-varenicline group received both nicotine and varenicline. At the end of week 3, the dorsal skin flaps were raised in all rats. On postoperative day 7, the flaps were evaluated by direct observation, microangiography, and light microscopy. The mean necrotic area of the flaps was significantly greater in the nicotine group than in the control group (49.2 +/- 4.71 vs. 22.03 +/- 0.93%, respectively, p < .01) and significantly higher in the nicotine-varenicline group than in the varenicline group (22.4 +/- 1.23 vs. 9.2 +/- 0.59%, respectively, p < .01). However, no significant difference was observed between the control and nicotine-varenicline groups (p = .934). Microangiographically, vascularity was lowest in the nicotine group and highest in the varenicline group. Histologically, larger areas of necrosis, more severe inflammation and less vessel formation were observed in the nicotine group. Healing, exhibited by a greater number of vessels, was evident in the varenicline-applied groups. Varenicline appears to increase the microcirculation of random flaps, as shown by decreased flap necrosis and increased vascularity.