Aims To test the efficacy and safety of varenicline as an aid to smoking cessation in methadone maintained smokers. Design Multicenter, randomized, double‐blind, placebo‐controlled trial with random assignment to 12 weeks of varenicline 1 mg twice daily (n=57) or matched placebo (n=55), with in‐person and telephone counseling. Setting Urban methadone programmes in the Bronx, New York City, New York, USA. Participants Methadone maintenance patients, smoking ≥5 cigarettes/day, interested in quitting, stable in methadone treatment, without current axis I psychiatric disorders, suicidal ideation, or recent suicide attempts. Measurements Seven‐day point prevalence abstinence verified by expired carbon monoxide (CO) < 8 p.p.m at week 12 (primary outcome); CO‐verified abstinence, cigarettes/day, incident axis I psychiatric illness, suicidal ideation or serious adverse events (SAEs) at weeks 2, 4, 8, 12 or 24 (secondary outcomes). Findings Baseline demographic, smoking and clinical factors were similar between groups. Retention at 24 weeks was 90%. Subjects receiving varenicline were more likely than those receiving placebo to achieve abstinence (10.5% v 0%, p = .03; effect size 10.5%, 95% CI 4.4 – 19.3%) and to reduce smoking (median 5 v 2 cigarettes/day, p<.001) at 12 weeks. These effects were not maintained after drug treatment ceased. Incident psychiatric illness (OR = 0.84, 95% CI 0.16, 4.4) and suicidality (OR = 0.88, 95% CI 0.2, 5.2) were not different between groups. There were no psychiatric or cardiac SAEs. Conclusions Varenicline can aid short‐term smoking abstinence in methadone maintained smokers.