BACKGROUND: Tobacco smoking remains the leading preventable cause of death among American women. Exercise has shown promise as an aid to smoking cessation because it reduces weight gain and weight concerns, improves affect, and reduces nicotine withdrawal symptoms and cigarette craving. Studies have shown that the practice of yoga improves weight control, and reduces perceived stress and negative affect. Yoga practice also includes regulation of breathing and focused attention, both of which may enhance stress reduction and improve mood and well-being and may improve cessation outcomes. METHODS/DESIGN: This pilot efficacy study is designed to examine the rates of cessation among women randomized to either a novel, 8-week Yoga plus Cognitive Behavioral Therapy (CBT) smoking cessation intervention versus a Wellness program plus the same CBT smoking cessation intervention. Outcome measures include 7-day point prevalence abstinence at end of treatment, 3 and 6 months follow up and potential mediating variables (e.g., confidence in quitting smoking, self-efficacy). Other assessments include measures of mindfulness, spirituality, depressive symptoms, anxiety and perceived health (SF-36). DISCUSSION: Innovative treatments are needed that address barriers to successful smoking cessation among men and women. The design chosen for this study will allow us to explore potential mediators of intervention efficacy so that we may better understand the mechanism(s) by which yoga may act as an effective complementary treatment for smoking cessation. If shown to be effective, yoga can offer an alternative to traditional exercise for reducing negative symptoms that often accompany smoking cessation and predict relapse to smoking among recent quitters. TRIAL REGISTRATION: ClinicalTrials NCT00492310.