Objective: To determine the comparative efficacy of quetiapine and divalproex for the treatment of adolescent mania. Method: Fifty adolescents (ages 12-18 years) with bipolar I disorder, manic or mixed episode, were randomized to quetiapine (400-600 mg/day) or divalproex (serum level 80-120 [micro]g/mL) for 28 days for this double-blind study, which was conducted from July 2002 through January 2004. The primary efficacy measure was change in Young Mania Rating Scale (YMRS) score across the study period. Results: Repeated measures analysis of variance using the last-observation carried forward data indicated no statistically significant group difference in YMRS scores across the 28 days of the study (p = 0.3). Mixed regression analyses (comparison of slopes) revealed that improvement in YMRS scores occurred more rapidly in the quetiapine than in the divalproex group for both the last-observation carried forward (p = 0.01) and observed data (p = 0.03). Response and remission rates were significantly greater in the quetiapine than in the divalproex group (p less than 0.03). Rates of adverse events did not differ significantly between groups. Conclusions: The results suggest that quetiapine is at least as effective as divalproex in the treatment of acute manic symptoms associated with adolescent bipolar disorder; however, a quicker reduction of manic symptoms may occur with quetiapine as compared with divalproex. Quetiapine may be useful as monotherapy for the treatment of adolescents with manic or mixed episodes, although placebo-controlled studies are necessary. (Contains 3 figures and 2 tables.)