The prevalence of smokeless tobacco use in the United States is low vs. cigarette smoking, yet rates have remained constant over the past few years. In contrast, the rate of smokeless tobacco use in India is 20%. Smokeless tobacco is a carcinogenic and responsible for ~10,000 deaths/year from oral cancer in India. Unfortunately, there have been remarkably few intervention trials in India for smokeless tobacco users. To date, no trial has evaluated the new FDA approved medication, varenicline, for smokeless tobacco use. We will conduct a randomized placebo-controlled trial of varenicline for smokeless tobacco dependence at the National Drug Dependence Treatment Center (NDDTC) at the All India Institute of Medicine (AIIMS) in New Delhi with 237 smokeless tobacco users. The primary aims of this trial are to: 1) enhance research capacity at the NDDTC (i.e., train AIIMS staff to implement the behavioral counseling protocol with pharmacotherapy, data collection and management procedures); 2) assess the efficacy of varenicline for increasing biochemically confirmed 7-day point prevalence smokeless tobacco quit rates at the end-of treatment; and 3) assess longitudinal patterns of relapse and recovery following treatment with varenicline. The results of this trial may guide future investments to evaluate the efficacy of varenicline for smokeless tobacco dependence in the US, which is critical since smokeless tobacco use in the US may increase in the coming years and no approved pharmacotherapy for this drug dependence exists in the US or around the globe.