Efficacy and tolerability of Hypericum LI 160 was compared to fluoxetine and placebo in mild to moderate Major Depression (DSM–IV) in a 4–week randomized, double–blind trial. One hundred and sixtythree outpatients from 15 general practitioner centers received either 900 mg Hypericum LI 160, 20 mg fluoxetine, or placebo daily. Amelioration was measured by the Hamilton and the Montgomery–Åsberg Depression scales. Response and remission rates and global ratings by investigators and patients were measured. Adverse event reports, laboratory screening, vital signs, physical exams and ECG were collected. No significant differences could be observed regarding efficacy measures except for remission rate (Hypericum 24%; fluoxetine 28%; placebo 7 %). Hypericum was significantly better tolerated than fluoxetine. Hypericum LI 160 or fluoxetine were not more effective in short–term treatment in mild to moderate depression than placebo.