Hypericum perforatum is a medicinal plant with established antidepressant properties. The aim of this meta-analysis was to compare the efficacy and tolerability of this antidepressant with selective serotonin reuptake inhibitors (SSRIs) as a group of standard antidepressants. For this purpose, Pubmed, Embase, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials were searched for studies comparing efficacy and/or tolerability of Hypericum with SSRIs in the management of major depressive disorder (MDD). The search terms were: "Hypericum" or "St. John's wort" and "fluoxetine", "paroxetine", "citalopram", "serteraline", "escitalopram", or "fluvoxamine". Data were collected from 1966 to 2008 (up to June). "Clinical response", "remission", "mean reduction in Hamilton Rating Scale for Depression (HAMD) score from baseline", "total adverse events", and "withdrawals due to adverse events" were the key outcomes of interest. Thirteen randomized placebo controlled clinical trials met our criteria and were included. Comparison of SSRIs with placebo yielded a significant relative risk (RR) of 1.22 (95% confidence interval: 1.03-1.45, P=0.02) for clinical response (n=4), a non significant RR of 0.96 (95% CI: 0.71-1.29, P=0.76) for remission (n=4), and a significant effect size [weighted mean difference (wmd+)] of 1.33 (95% CI: 1.15-1.51, P<0.0001) for mean reduction in HAMD score from baseline (n=3). Comparison of Hypericum with SSRIs yielded a non significant relative risk (RR) of 0.99 (95% confidence interval: 0.91-1.08, P=0.83) for clinical response, a non significant RR of 1.1 (95% CI: 0.90-1.35, P=0.35) for remission, and a non-significant wmd+ of 0.32 (95% CI: -1.28-0.64, P=0.52) for mean reduction in HAMD score from baseline, a non significant RR of 0.85 (95% CI: 0.7-1.04, P=0.11) for any adverse events, and a significant RR of 0.53 (95% CI: 0.35-0.82, P=0.004) for withdrawals due to adverse events. Hypericum does not differ from SSRIs according to efficacy and adverse events in MDD. Lower withdrawal from study due to adverse events by Hypericum is an advantage in management of MDD.