Fifteen adolescents and young adults (ages 16–24) with a DSM-III-R diagnosis of major depression, who failed to respond to prior treatment with tricyclic antidepressants, were treated in an open trial using fluoxetine. Of the 11 patients who completed a 6–7 week trial, 64% showed a therapeutic response (≥50% change) on the Hamilton Depression Rating Scale (HDRS), and 73% showed a positive response when rated by the Clinical Global Impression Scale (CGI). Side effects generally were mild, and the most common were tremor, dry mouth, nausea, sweating, and decreased appetite. Sweating, drowsiness, dry mouth, tremor, and alopecia appeared more commonly than in adult studies. One patient became manic, and none showed an increase in suicidal ideation. A starting dose of 20 mg daily often was tolerated poorly, and patients generally did better with 5–10 mg daily for the first week. Some patients appeared to exhibit antidepressant responses on 5–10 mg daily. These preliminary data suggest that fluoxetine, in doses ranging from 5 to 40 mg daily, when used in combination with psychosocial treatments, may be an effective antidepressant in adolescents or young adults who have not previously responded to adequate tricyclic therapy. Double-blind placebo-controlled studies are needed to evaluate the potential efficacy of fluoxetine in treating major depression in adolescents and young adults.