Objectives: Varenicline is a partial agonist at the α2β4 and α6β2 nAChR receptors and a full agonist at α7 receptors. Both α7 and α6β2 receptors are implicated in the neural reward circuitry activated by cocaine use. A preliminary clinical trial suggested that varenicline treatment reduced cocaine use. This trial was intended to replicate and extend the findings of the previous trial. Methods: This was a 12-week, double-blind, placebo-controlled clinical trial involving 156 subjects with DSM IV cocaine dependence. Subjects received up to 2 mg of varenicline or identical placebo daily along with weekly relapse prevention psychotherapy. The primary outcome measure was cocaine use measured by thrice-weekly urine drug screens. Additional outcome measures included end of study cocaine abstinence, cocaine craving, cocaine withdrawal symptom severity, cigarette use, and global improvement measure by the Clinical Global Improvement Scale. Results: End of study cocaine abstinence, measured by urine drug screens during the last 3 weeks of the trial, was not different between groups (8% in the varenicline treated subjects and versus 9% in placebo-treated subjects). Generalized estimating equations analysis of urine drug screen results showed no significant difference between groups in cocaine abstinence over the 12 weeks of the trial. There were no significant differences between the 2 groups in cocaine craving or cocaine withdrawal symptom severity. Varenicline was well-tolerated. There were no medication-associated serious adverse events. Conclusions: Varenicline plus cognitive-behavioral therapy does not seem to be an efficacious treatment for cocaine dependence.