This study examined changes in tobacco craving, withdrawal, and affect as correlates of efficacy in a phase-2 clinical trial of varenicline for smokeless tobacco dependence in India. Smokeless tobacco users (N = 237) at the All India Institute of Medical Sciences were randomized to placebo or varenicline. Abstinence was defined as cotinine-verified seven-day point prevalence cessation at end of treatment (EOT). General Linear Model repeated measures assessed the effects of treatment condition, time, abstinence state, and interaction effects on changes in craving, withdrawal, positive (PA) and negative affect (NA) from baseline to EOT. All participants showed a significant reduction in withdrawal (p < .001), total craving (p < .001), positive reinforcement (PR) craving (p < .001), and NA (p = .02), and an increase in PA (p = .04) from baseline to EOT. However, there were no differences between placebo and varenicline participants in measures of withdrawal, craving, or affect from baseline to week 3 or at EOT. Significant interactions between time and abstinence state were found for total craving (p = .008), PR craving (p < .001), and withdrawal (p = .001), indicating reductions in these processes among those abstinent vs. those still chewing smokeless tobacco. Additional research is needed concerning the effects of varenicline on craving, withdrawal, and affect among smokeless tobacco users.