--- - |2 1) Cigarette smoking was independently associated with poorer survival, regardless of American Joint Committee on Cancer stage. 2) Nicotine progressively decreased microRNA (miR)‐200c expression in a time‐ and dose‐dependent manner in colorectal cancer (CRC) cells. 3) Nicotine promoted proliferation, migration, and invasion and the epithelial–mesenchymal transition in CRC cells, though overexpression of miR‐200c abrogated these nicotine‐induced effects. Background Cigarette smoking is the most well‐established risk factor for colorectal cancer (CRC). However, the mechanisms of smoking‐associated colorectal carcinogenesis are poorly understood. Methods The effects of prediagnosis tobacco use on clinical characteristics, overall survival (OS), and recurrence‐free survival (RFS) were analyzed in 396 patients with CRC. Associations between smoking status and OS and RFS were evaluated using Cox’s proportional hazards regression. Furthermore, the effects of nicotine on the CRC cell lines SW620 and HT‐29 were evaluated using in vitro assays. Results “Ever smoking” was associated with elevated serum carcinoembryonic antigen, American Joint Committee on Cancer T category, metastasis, and poorer OS and RFS in patients with CRC (OS: hazard ratio [HR] = 1.74, 95% confidence interval [CI], 1.07–2.81, p = 0.025; RFS: HR = 1.66, 95% CI: 1.18–2.34, p = 0.004). MicroRNA (miR)‐200c was downregulated in CRC and tumor‐adjacent tissues from ever smokers compared with the corresponding tissues from never smokers with CRC. Nicotine inhibited miR‐200c expression in a dose‐ and time‐dependent manner in SW620 and HT‐29 CRC cell lines. Nicotine induced cell proliferation, migration, and invasion and promoted the epithelial–mesenchymal transition in SW620 and HT‐29 cells, and these effects were attenuated by overexpression of miR‐200c. Conclusion Our findings support the adverse effects of prediagnosis cigarette smoking on prognosis and clinical behavior in CRC. We demonstrate a novel oncogenic mechanism by which nicotine promotes growth and metastasis in CRC by downregulating miR‐200c. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1369-1379, February 2019. '