Abstract contenBackground: Smoking is a chronic disease and one of the main causes of years of life lost or years lived with disability and is considered worldwide the main cause of preventable death. Aims: To review the efficacy and safety of cytisine for smoking cessation. Design: were previously established (PROSPERO ID: CRD42022296780); an exhaustive search was carried out in different databases, identifying randomized controlled trials (RCTs). Settings: health centers of any level. Participants: persons of any age or gender, smokers. Interventions: cytisine at standard dosage versus placebo, varenicline, and nicotine replacement therapy (NRT). Findings: We identified 12 RCTs. Eight RCTs compared cytisine to placebo at the standard dose (RR= 2.25, 95% CI 1.40 to 3.62; I²= 90%). Following sensitivity analysis, we pooled the findings of five RCTs evidencing that cytisine is an effective treatment for smoking cessation,  increasing the chances of quitting We pooled the findings of five RCTs which contributed to the primary analysis covering 2134 patients, 1099 of whom took cytisine, and indicates that cytisine at the standard dosage is an effective smoking cessation treatment that increases the chances of quitting compared to placebo (smoking cessation rate at longest follow-up: RR= 3.46, 95% CI 2.45 to 4.89; participants = 2134; I²= 18%; smoking cessation rate at least six months: RR of 3.40 (95% CI 2.17 to 5.32); participants = 1938; I²= 35%; low-quality evidence). We estimate an NNT of 6. Two trials compared the efficacy of cytisine versus NRT and the combination of both studies yields modest results in favor of cytisine. Three trials compared cytisine versus varenicline, without a clear benefit for cytisine. Meta-analyses of all non-serious AEs in the cytisine group versus placebo groups yielded a RR of 1.24 (95% CI 1.11 to 1.39; participants = 5895; studies = 8; I² = 0%; high-quality evidence). Conclusions: cytisine increased the chances of successful smoking cessation by more than three-fold compared with placebo. Cytisine had a benign safety profile, with no evidence of serious safety concerns. Limited evidence suggests that cytisine may be more effective than NRT, with modest cessation rates. [O1]