A prospective, randomized, multicentre, double-blind placebo controlled study is described which compares the ecacy and tolerability of hypericum administered as a concentrated ethanolic extract of St John's wort (ZE117) to patients with mild±moderate depression (ICD-10; F 32 . 0 mild; F 32 . 1 moderate). Patients on active medication received 250 mg extract tablets twice daily, corresponding to 1 mg hypericin daily, for 6 weeks. The primary ecacy variable was the 21 item Hamilton Depression Scale (HAMD); secondary variables were the risk-bene®t Clinical Global Impression (CGI) scales I±III and a validated patient self-assessment on a Visual Analogue Scale (VAS). 162 patients entered the trial. 159 patients (80 on active medication) were evaluated in an intention-to-treat analysis; 136 patients (66 on active medication) in a protocol-compliant analysis. Patients in the two treatment groups did not dier with respect to the distribution of age, gender, weight and height. Based on dierences in HAMD scores ( p 5 0 . 001), both the intention-to-treat and protocol-compliant analyses demonstrate that ZE117 is clinically eective in the treatment of patients with mild to moderate depression following 6 weeks' treatment. Using the criteria of 550% reduction in HAMD score from baseline and/or an actual HAMD score 410 as evidence of a clinically relevant response, 56% patients treated with ZE117 were classi®ed as responders, compared with 15% patients on placebo. The secondary ecacy variables data con®rmed these ®ndings. Compliance was high; using electronic devices within the medication containers, a therapeutic coverage of 81 . 7% was found. This was probably due, in part, to the low number of adverse events reported (11 total, 5 placebo, 6 active), the majority of which were transient, self-limiting and, in the case of active treatment, mostly non-speci®c gastrointestinal complaints. These results demonstrate that hypericum (ZE117) provides a safe and eective treatment for patients with mild to moderate depression. The good tolerability pro®le contributes to the high observed compliance, possibly conferring a clinical advantage in achieving ecacy over other antidepressants with less favourable side eect pro®les.