Research evaluating the relationship of comorbidity to treatment outcome for panic disorder has produced mixed results. The current study examined the relationship of comorbid depression and anxiety to treatment outcome in a large-scale, multi-site clinical trial for cognitive-behavior therapy (CBT) for panic disorder. Comorbidity was associated with more severe panic disorder symptoms, although comorbid diagnoses were not associated with treatment response. Comorbid generalized anxiety disorder (GAD) and major depressive disorder (MDD) were not associated with differential improvement on a measure of panic disorder severity, although only rates of comorbid GAD were significantly lower at posttreatment. Treatment responders showed greater reductions on measures of anxiety and depressive symptoms. These data suggest that comorbid anxiety and depression are not an impediment to treatment response, and successful treatment of panic disorder is associated with reductions of comorbid anxiety and depressive symptoms. Implications for treatment specificity and conceptual understandings of comorbidity are discussed.