Chronic cigarette smoking affects many tissues negatively. Nicotine in tobacco has negative effects on tissues, kidneys, and eyes especially, where microcirculation is vitally important for the survival and functioning. It is known that appropriate vascular endothelial growth factor (VEGF) and (matrix metalloproteinase 2) MMP2 levels are required for suitable vascularity and enough microcirculation. The aim of this study was to investigate the effect of nicotine on VEGF and MMP2 levels in kidney and eyes, where microcirculation is very important for their function. The nicotine was given into drinking water, to male and female rats for 6 weeks. During the first 2 weeks, the nicotine concentration was 10 mg/L, then was given at a fixed dose of 20 mg/L until the end of the experiment. The VEGF and MMP2 levels were increased in kidney tissue of both genders as a result of given nicotine. MMP2 levels were also increased in the eye tissue for both genders similarly. However, VEGF levels increased in the eye tissue with nicotine in males, whereas it did not change in females. The use of nicotine made VEGF and MMP2 levels increase in kidney tissue in both genders of rats. This increase in VEGF was observed only in male eye tissue, not in females. According to our findings, it can be suggested that nicotine has negative effects on microvascular circulation by increasing VEGF and MMP2 levels. In addition, it should be pointed out that estrogen might have protective effects on female eye tissue. Further studies are necessary to understand the complex relationship between the role of nicotine and estrogen on eye and kidney tissues.