Tobacco smoking is a global pandemic that poses substantial health burdens and costs. With nearly six million deaths annually, smoking is the single most important cause of avoidable premature mortality in the world, mainly from lung cancer, coronary heart disease, chronic obstructive pulmonary disease and stroke. Smoking is a very difficult addiction to break, even for those with a strong desire to quit. Electronic cigarettes are an attractive long-term alternative source of nicotine to conventional cigarettes because of their many similarities with smoking. Electronic cigarette users report buying them to reduce cigarette consumption, to relieve tobacco withdrawal symptoms, to quit, and to continue having a ‘smoking’ experience, but with reduced health risks. Actually, there aren’t antismoking treatments for people who smoke only electronic cigarette (single users) or electronic cigarette and classic cigarette (dual users). There isn’t any specific information on the efficacy and safety of new pharmacological support for electronic cigarette users. We propose that smoking cessation with varenicline plus counselling delivered to electronic cigarette users could be associated with similar smoking abstinence rates compared to the results obtained in the general population. Herein, we describe the methodology of a double-blind, placebo-controlled, randomized clinical trial, of 24 weeks duration, that examines the efficacy of varenicline (1 mg BID – for 12 weeks) plus counselling compared to matched placebo (1 mg BID – for 12 weeks) plus counselling.