In this double-blind, randomized, placebo-controlled, prospective study, the clinical efficacy and tolerability of oral Hypericum extract STW 3-VI (Laif®) 900 mg once daily was compared with that of placebo. A total of 140 outpatients (94 women; 46 men) with moderate depressive disorders and a 17-item Hamilton Depression Scale (HAMD-17) score of 20 to 24 were enrolled in this study. Following a single-blind placebo run-in period of 7 days, the patients were randomized to Hypericum extract 900 mg or placebo for the 6-week treatment period. Nineteen patients have been excluded from the per protocol collective because of violations of protocol regarding the scheduling of study visits and intake of study medication. The primary endpoint for treatment efficacy was the change in total HAMD-17 score at the end of the 6-week treatment period. The HAMD-17 total score decreased significantly from baseline by approximately 11.1 ±4.5 points (from 22.8±1.1 to 11.8±4.4) in the Hypericum group and by approximately 3.4±3.9 points (from 22.6±1.2 to 19.2±3.8) in the placebo group (P<.001). Comparable group differences in favor of Hypericum were revealed by an additional responder analysis, the von Zerssen's Adjective Mood Scale, the Clinical Global Impressions scale, and a global efficacy assessment. Tolerability was very good in both groups; neither serious adverse events nor clinically relevant changes in safety parameters were observed, and only 2 cases demonstrated a possible connection between an adverse event and the study medication. The final safety assessment showed no differences between the Hypericum extract and placebo groups. The study provided evidence that Hypericum extract STW 3-VI in a once-daily dosing regimen may be an effective and well-tolerated option for patients with moderate depressive disorders.