 In the United States, approximately 7.7 million individuals older than 12 years of age report current past month use of smokeless tobacco ST. ST use has been associated with oral and extra-oral cancer as well as cardiovascular and cerebrovascular disease. To date, no pharmacotherapies have been shown to increase long-term 6 months abstinence rates in ST users. Novel pharmacotherapies that decrease withdrawal symptoms and nicotine self-administration need to be tested in ST users. Varenicline ChantixTM, Pfizer is a novel selective nicotinic receptor partial agonist with specificity for the α4β2 nicotine acetylcholine receptor that has demonstrated remarkable efficacy for increasing long-term tobacco abstinence rates in cigarette smokers. The novel mechanism of action of varenicline potentially circumvents the limitations of using nicotine replacement therapy or bupropion pharmacotherapy in ST users. The overall goal of this line of research is to develop effective pharmacologic treatments for ST users to increase long-term 6 months abstinence rates. The central hypothesis of this application is that varenicline is efficacious for the treatment of ST users. To evaluate this hypothesis, we will conduct a pilot study to obtain preliminary estimates of efficacy of 12-weeks of varenicline for increasing the prolonged and point prevalence tobacco abstinence rates at 12 weeks end-of-treatment in ST users. We will also evaluate the effect of varenicline on nicotine withdrawal symptoms and tobacco craving. If the results are promising, we will plan for a multicenter, randomized, double-blinded, placebo-controlled clinical trial with the Oregon Research Institute in Eugene, OR, to investigate the efficacy of varenicline to increase long-term 6 months abstinence rates in ST users. 