Tobacco and cannabis are commonly used together in the Veteran population and result in significant morbidity; to date, however, advancements in medication development for this comorbidity have been limited. Varenicline, a selective nicotinic nACH receptor partial agonist of the α4β2 subtype and a full agonist of the α7 subtype, is arguably the most effective pharmacotherapy for promoting tobacco abstinence and has also shown promise for the treatment of alcohol use disorder. Varenicline may improve cannabis use outcomes through multiple mechanisms, including interaction with the mesolimbic dopamine system, enhancement of cognitive functioning, and restoration of inhibitory control. Our pilot data also suggests that varenicline may be effective in improving use outcomes in individuals who use both cannabis and tobacco. Given the prevalence of cannabis and tobacco use disorder in Veterans, we propose to conduct a 12-week, placebo-controlled trial in 138 individuals to evaluate the potential efficacy of varenicline in individuals with this comorbidity. Primary outcomes will be reduction in cannabis and tobacco use, and exploratory analyses will examine retention in treatment.