Background: There is a lack of evidence about the effectiveness of cognitive behavior therapies (CBT) in settings of routine clinical care as well as in the treatment of panic and comorbid disorders. Methods: We investigated a group-oriented CBT approach for 80 patients with panic disorder including 35 patients with current comorbid major depression. Assessments took place 6 months before treatment, at the beginning and end of treatment, and 1 year later. Structured interviews and multiple clinical self-rating scales were used. Results: Panic patients with comorbid major depression showed higher anxiety-specific and nonspecific pathology. The most striking benefits were in reducing avoidance behavior, while improvements concerning catastrophic beliefs were smaller, but still significant. For most self-rating scale results, patients with and without comorbid depression improved to a comparable degree. However, the end-state functioning of patients with panic disorder and current comorbid depression at admission is significantly lower than for patients with panic disorder alone. Conclusions: The results point to the necessity to develop and improve treatment approaches for patients with comorbidity of panic disorder and current major depression.