Adolescents with depression and high levels of oppositionality often are particularly difficult to treat. Few studies, however, have examined treatment outcomes among youth with both externalizing and internalizing problems. This study examines the effect of fluoxetine, cognitive behavior therapy (CBT), the combination of fluoxetine and CBT, and placebo on co-occurring oppositionality within a sample of depressed adolescents. All treatments resulted in decreased oppositionality at 12 weeks. Adolescents receiving fluoxetine, either alone or in combination with CBT, experienced greater reductions in oppositionality than adolescents not receiving antidepressant medication. These results suggest that treatments designed to alleviate depression can reduce oppositionality among youth with a primary diagnosis of depression.