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To compare the effectiveness of varenicline with nicotine replacement for smoking cessation and to evaluate the safety and effectiveness of varenicline in people with mental illness.Evaluation of consecutive routine cases before and after the introduction of varenicline.National Health Service (NHS) tobacco dependence clinic in London, UK.A total of 412 cases receiving routine care.Seven group support sessions over 6 weeks with either nicotine replacement therapy (NRT) (n = 204) or varenicline (n = 208).Verified abstinence 4 weeks after quit day, severity of withdrawal symptoms, incidence and severity of adverse drug symptoms, cost per patient treated and cost per successful short-term quitter.Short-term cessation rates were higher with varenicline than NRT (odds ratio = 1.70, 95% confidence interval = 1.09–2.67). Varenicline was equally effective in those with and without mental illness. Craving to smoke, but not adverse mood, was less severe with varenicline than NRT. The cost per quitter was similar for varenicline and NRT. There was a higher incidence of adverse drug symptoms among those taking varenicline, but these were tolerated by most smokers. There was no evidence that varenicline exacerbated mental illness.In this setting and with group support varenicline appears to improve success rates over those achieved with NRT, and is equally effective and safe in those with and without a mental illness.