Smoking is the major avoidable cause of preventable morbidity and premature mortality in the UK and internationally. Smoking is also the principal cause of health inequalities and is responsible for most of the difference in healthy life-expectancy between the richest and poorest in our society and those with and without mental health problems. It has been estimated that smoking-related illnesses cost the NHS approximately £5bn per year. Varenicline has been shown to be the most clinically effective smoking cessation medicine for short-term abstinence in randomized controlled trials (RCTs). However, there is very little evidence for its long-term effectiveness and impact on clinical outcomes which are relevant to the NHS.