After anxiety, depression is one of the most common psychiatric diseases, showing a lifetime prevalence of 4.4 - 18 %. St. John's Wort is a herbal antidepressant combining a long tradition of use with well-proven medical research. We conducted a meta-analysis to review St. John's Wort's place in the treatment of depression. A comprehensive literature search was conducted for studies comparing effectiveness and tolerability of St. John's Wort with either placebo or synthetic antidepressant. Thirty studies met the inclusion as well as the quality criteria and were included in the meta-analysis. Four studies consisted of all three arms and were thus included in both analyses. Our results demonstrated a significant advantage for St. John's Wort compared to placebo (n = 2129, RR = 0.66, 95 % CI 0.57 - 0.78, p < 0.00001, NNT = 4.2 95 % CI 3.0 - 6.6, mean response: 53.3 vs. 32.7 %). Compared to synthetic antidepressants St. John's Wort demonstrated similar effectiveness (n = 2231, RR = 0.96, 95 % CI 0.85 - 1.08, p = 0.5, mean response: 53.2 % vs. 51.3 %). In the sub-group of mild to moderate depression, corresponding with the indication for St. John's Wort assigned by the German health authority, the herbal antidepressant showed better results against the synthetic antidepressants (n = 1166, RR = 0.85, 95 % CI 0.75 - 0.97, p = 0.01, NNT = 14.3, 95 % CI 8.3 - 100, mean response 59.5 vs. 52.9 %). This result viewed together with St. John's Wort's favourable side-effects profile, leading to a lower rate of drop-outs, suggests treatment with St. John's Wort should be attempted for milder forms of depression. Funnel plot analysis suggested publication bias could exist for the comparison with placebo. To put this in a perspective the fail-safe-N-test calculated that 423 studies with no effect would be needed to negate the presented result for placebo studies.