AIMS: To determine the effectiveness and safety of varenicline in treating tobacco dependence in patients with severe mental illness.DESIGN: A systematic review and meta-analysis of randomised controlled trials that compared varenicline with a placebo or an alternative intervention for smoking cessation or reduction.SETTING: Both in-patient and out-patient settings in any country.PARTICIPANTS: Adult patients aged 18 and over with any type of severe mental illness. The systematic review included eight studies comprising 398 participants.MEASURES: Primary outcome measures were (1) smoking cessation (2) smoking reduction measured by changes in the number of cigarettes smoked per day and (3) number of psychiatric adverse events, which were collected at the end of treatment.FINDINGS: The random-effect pooled estimates from the five studies that reported smoking related outcomes found that varenicline is statistically superior to placebo in smoking cessation (risk ratios 4.33; 95% CI: 1.96-9.56), and smoking reduction was higher in varenicline groups (mean reduced daily cigarettes was 6.39; 95% CI: 2.22-10.56). There is no significant difference regarding neuropsychiatric and other adverse events.CONCLUSIONS: Varenicline appears to be significantly more effective than placebo in assisting with smoking cessation and reduction in people with severe mental illness. There appears to be no clear evidence that varenicline was associated with an increased risk of neuropsychiatric or other adverse events compared with placebo. This article is protected by copyright. All rights reserved.