This pilot study examined the effectiveness, safety, tolerability, and pharmacodynamics of Hypericum perforatum (St. John's wort) in the treatment of youths diagnosed with major depressive disorder. Youths 6 to 16 years of age meeting DSM-IV criteria for major depressive disorder with depressive symptoms of at least moderate severity were eligible to enroll between January 1999 and January 2001 in this 8-week, prospective, open-label, outpatient study. Outcome measures included the Children's Depression Rating Scale-Revised (CDRS-R) and the Clinical Global Impressions (CGI) scale. A priori criteria for response consisted of a CDRS-R score of </=28 and a CGI severity score </=2. Patients were initially prescribed 150 mg St. John's wort three times daily. If at the end of week 4 the patient did not meet a priori response criteria, the dose was increased to 300 mg three times daily. Thirty-three youths with a mean (SD) age of 10.5 (2.9) years were enrolled. After 4 weeks of St. John's wort therapy, 22 youths had their dose increased to 900 mg/day. Twenty-five of the patients met response criteria after 8 weeks of treatment. Overall, St. John's wort was well tolerated. St. John's wort may be an effective treatment for youths diagnosed with major depressive disorder. Placebo controlled trials seem indicated.