Objective To compare the safety of agomelatine and selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression.Methods Retrieved literatures in the database at home and abroad from the built of the databases to March in 2016.The databases included Pubmed,Cochrance library,CNKI,Wanfang database and VIP database.Two researchers selected literatures,evaluated quality and extracted data independeatly.5.3.5 RevMan software was used to analyze.Result 87 literatures were retrieved,and nine English literatures and two Chinese literatures were included.Agomelatine had a lower risk than paroxetine in insomnia (RR:0.40,95％ CI:[0.17,0.92],P=0.03) and sexual dysfunction (RR:0.13,95％ CI:[0.04,0.39],P=0.0003),than fluoxetine(RR:0.68,95％ CI:[0.48,0.96],P=0.03) and paroxetine(RR:0.37,95％ CI:[0.25,0.55],P＜0.01) in nausea and vomiting,and than escitalopram in sweating(RR:0.34,95％ CI:[0.13,0.85],P=0.02) and headaches(RR:0.63,95％ CI:[0.43,0.91],P=0.01).The difference of them was statistically significant.Agomelatine had a higher risk than sertraline (RR:4.65,95％ CI:[1.02,21.16],P=0.05) in drowsiness,and than escitalopram in constipation (RR:3.46,95％ CI:[1.16,10.36],P=0.03),the difference was statistically significant too.Compared agomelatine and SSRIs,the occurrence risk of dry mouth and diarrhea were no significant difference.Conclusion Both agomelatine and selective serotonin reuptake inhibitors (SSRIs) had its pros and cons in terms of safety.Safety of agomelatine is better than paroxetine.Agomelatine and escitalopram had its own advantages and disadvantages respectively in safety.The evidence of the safety among agomelatine,fluoxetine and sertraline need further explore.