Selective serotonin reuptake inhibitors (SSRIs) like paroxetine have replaced older antidepressants mainly because of a more favorable safety profile, but they are still associated with burdensome side effects. We investigate the tolerability of St. John's wort extract WS 5570, a herbal antidepressant with proven efficacy, in comparison to paroxetine and other SSRIs and placebo. A reanalysis was performed based on the original data from four controlled clinical trials during which 1661 outpatients with major depression (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria) received between 600 and 1800 mg/day WS 5570 (n=1264), 20 or 40 mg/day paroxetine (n=126), or placebo (n=271) for 6 weeks. For single and grouped adverse events, the risk ratios for treatment group comparisons were determined along with their 95% confidence intervals, including comparisons with published data for SSRIs. Across the four trials, the percentage of patients with any adverse events under WS 5570 exposition was comparable with placebo [risk ratio (95% confidence interval): 1.1 (0.9-1.3) in favor of WS 5570] and significantly lower than for paroxetine [2.4 (2.1-2.8)]. Compared with the herbal extract adverse event rates under paroxetine were between 10 and 38-fold higher (point estimates) in five out of seven symptom clusters inspected. WS 5570 was devoid of effects of sedation, anticholinergic reactions, gastrointestinal disturbances, and sexual dysfunction often found during treatment with SSRIs and other synthetic antidepressants. In conclusion, WS 5570 exhibits substantially lower incidence rates of adverse events than paroxetine and other SSRIs.