--- - |2- (1) Rosmarinic acid plays a protective role in nicotine‐induced atherosclerosis. (2) Rosmarinic acid downregulates nicotine‐induced C‐reactive protein expression by inhibiting ROS‐mediated NLRP3 inflammasome activation in rat vascular smooth muscle cells. Atherosclerosis is widely known to be a chronic inflammatory disease. C‐reactive protein (CRP), an important inflammatory factor, plays an essential role in the pathogenesis of atherosclerosis. Nicotine, the main addictive component of cigarette, has been shown to induce the production of CRP. The aim of this study was to investigate the effect of rosmarinic acid (RA), a polyphenol with antiinflammatory activity, on nicotine‐induced elevation of CRP in vascular smooth muscle cells (VSMCs). We found that pretreatment of VSMCs with RA attenuated nicotine‐induced expression of CRP in a time‐ and dose‐dependant manner. In addition, RA also inhibited the activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome and reactive oxygen species (ROS) production resulting from nicotine treatment in VSMCs. To confirm these findings in vivo, we constructed a nicotine‐induced atherosclerosis rat model. RA did not significantly reduce the serum nicotine level of the rats, whereas it significantly decreased the levels of serum lipids, including concentrations of cholesterol, triglycerides, and low‐density lipoprotein cholesterol, and the serum level of CRP. RA also led to diminished nicotine‐induced activation of NLRP3 inflammasome and elevation in the CRP level in the aortic tissue of the model rats. The results of this study suggested a protective role of RA in nicotine‐induced atherosclerosis by inhibiting the ROS–NLRP3 inflammasome–CRP axial, and RA therefore represented a potential effective therapeutic approach to atherosclerosis, in particular for those who smoke. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1758-1767, February 2019. '