A recent pre-clinical study has shown that brain-penetrating statins can reduce risks of relapse to cocaine and nicotine addiction in rats. Based on this information, we conducted a randomized, double-blind, placebo-controlled, proof-of-concept trial to assess the efficacy of simvastatin in smoking cessation. After informed consent, 118 participants received behavioral cessation support and were randomly assigned to a 3-month treatment with simvastatin or placebo. The primary outcome was biochemically verified abstinence or smoking reduction at 3-month post-target quit date (TQD). Secondary outcomes were abstinence during weeks 9-12 post-TQD, prolonged abstinence or reduction at months 6 and 12 post-TQD, safety and craving assessed at each visit during the 3-month period of treatment. Simvastatin treatment was not associated with higher 3-month abstinence or smoking reduction compared to placebo. There was no significant difference in any of the secondary outcomes. Simvastatin was well tolerated. Over 3 and 9 months follow-up period, 78% simvastatin and 69% placebo participants were retained in the study. At 6 and 12 months, smoking remained significantly reduced from baseline in both groups. Our results demonstrate that a 3-month simvastatin treatment (40 mg/day), added to individual behavioral cessation support, does not improve significantly smoking cessation compared to placebo in humans. According to the World Health Organization, smoking is the largest preventable cause of disease and death in the world 1. Although the prevalence of everyday tobacco use has dropped in most nations since 1990, the total number of smokers has increased 2. In 2015, 6.4 million deaths worldwide were attributable to smoking, representing a 4.7% increase in smoking-attributable deaths since 2005. This number is likely to reach 8 to 10 millions a year by 2030 1,2. The benefits of smoking cessation have been clearly proven in terms of morbidity and mortality for different diseases related to tobacco, especially for lung cancer 3,4. Although over 70% of smokers want to quit, less than 5% of quit attempts are successful annually 5. Currently, there are only 3 first-line approved medications in the USA and Europe for smoking-cessation: nicotine replacement therapy (NRT), sustained release bupropion, and varenicline, which are widely recommended in many national guidelines. Nevertheless, the therapeutic effectiveness of NRT is relatively modest, bupropion is not widely used because of its safety profile and varenicline's use is limited because of fear of potential cardio-vascular or neuropsychiatric adverse effects 6,7. Therefore, the discovery of new medications that could facilitate abstinence and reduce relapse to cigarette use represents a pressing necessity to reduce risks associated with tobacco smoking. We recently reported in rats that brain-penetrating statins-simvastatin and atorvastatin-can reduce risks of relapse to addiction 8. In fact, chronic treatment with low doses of statins daily during a 21-day period of abstinence , significantly reduced cocaine or nicotine seeking compared with placebo without altering seeking for food. Based on this information, we hypothesized that simvastatin could have beneficial effects on smoking cessation in