OBJECTIVE: To examine initial response to treatment in a large sample of acutely manic bipolar I adolescents and to examine potential predictors of nonresponse, such as the presence of prominent depressive features, psychosis, or psychiatric comorbidity. METHOD: Adolescents, 12 to 18 years of age, with an acute manic episode were treated with open lithium. Response was defined as a decline in Young Mania Rating Scale total score of >or=33% and a rating of "much improved" or "very much improved" on the Clinical Global Impressions Improvement item at week 4. Remission of mania was defined as a Young Mania Rating Scale score of <or=6. Axis I diagnoses were assessed using the Lifetime Schedule for Affective Disorders and Schizophrenia for Adolescents. RESULTS: Of 100 subjects, 63 met response criteria and 26 achieved remission of manic symptoms at the week 4 assessment. Prominent depressive features, age at first mood episode, severity of mania, and comorbidity with attention-deficit/hyperactivity disorder did not distinguish responders from nonresponders. When treated with adjunctive antipsychotic medication, subjects with psychotic features at baseline responded as well as subjects without psychosis. CONCLUSIONS: In this largest systematic treatment trial of acutely manic adolescents to date, lithium appears effective for acute stabilization of symptoms. Controlled treatment studies in adolescents with acute mania are needed.