AIM OF STUDY: Depression is a psychiatric disorder. Chaihu-Shugan-San (CSS) is a traditional Chinese medicine formula suggested in the treatment of depression, but its effectiveness and safety are not well defined. This meta-analysis aimed to assess the effectiveness and safety of CSS in depression therapy. MATERIALS AND METHODS: The databases including MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, CNKI database, Wanfang Data and VIP Information were searched. Papers were reviewed systematically by two researchers and were analyzed using Cochrane software Revman 5.0. RESULTS: Ten randomized controlled trials comparing 835 subjects were included. Of these studies, seven studies used fluoxetine (20 mg, once a day), two used paroxetine (20 mg, once a day) and one used doxepin (25 mg, two times a day) as the antidepressant drugs. Meta-analyses revealed that CSS in combination with antidepressant drugs treatment significantly improved depressive symptoms (WMD=-3.56; 95% CI -5.09 to -2.03) and significantly increased effective rate (OR=3.31; 95% CI 1.80-6.10) and recovery rate (OR=2.32; 95% CI 1.61-3.34) compared with antidepressant drugs therapy. In addition, the efficacy of CSS as monotherapy was significantly better than antidepressants in improving depressive symptoms (WMD=-3.09; 95% CI -5.13 to -1.06) and in creasing effective rate (OR=2.61; 95% CI 1.23-5.53). CSS was comparable to antidepressants in increasing recovery rate (OR=1.83; 95% CI 0.84-3.98). No serious adverse events were reported in any of the included trials. CONCLUSION: The present work supported that CSS was effective and safe in treating depressed patients. More full-scale randomized clinical trials with reliable designs are recommended to further evaluate the clinical benefit and long-term effectiveness of CSS for the treatment of depression.