German researchers conducted a meta-analysis to review Hypericum perforatum’s place in the treatment of depression. A comprehensive literature search was conducted for studies comparing effectiveness and tolerability of H. perforatum with either placebo or synthetic antidepressants. Thirty studies met the inclusion criteria. Four studies consisted of all three arms and were thus included in both analyses. The results demonstrated a significant advantage for H. perforatum 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 H. perforatum 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 subgroup of mild to moderate depression, corresponding with the indication for H. perforatum assigned by the German health authority, the herbal antidepressant showed better results than 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%).