BACKGROUND: Interpersonal psychotherapy (IPT) seems to be as effective as cognitive behavioral therapy (CBT) in the treatment of major depression. Because the onset of panic attacks is often related to increased interpersonal life stress, IPT has the potential to also treat panic disorder. To date, a preliminary open trial yielded promising results but there have been no randomized controlled trials directly comparing CBT and IPT for panic disorder.MethodThis study aimed to directly compare the effects of CBT versus IPT for the treatment of panic disorder with agoraphobia. Ninety-one adult patients with a primary diagnosis of DSM-III or DSM-IV panic disorder with agoraphobia were randomized. Primary outcomes were panic attack frequency and an idiosyncratic behavioral test. Secondary outcomes were panic and agoraphobia severity, panic-related cognitions, interpersonal functioning and general psychopathology. Measures were taken at 0, 3 and 4 months (baseline, end of treatment and follow-up). RESULTS: Intention-to-treat (ITT) analyses on the primary outcomes indicated superior effects for CBT in treating panic disorder with agoraphobia. Per-protocol analyses emphasized the differences between treatments and yielded larger effect sizes. Reductions in the secondary outcomes were equal for both treatments, except for agoraphobic complaints and behavior and the credibility ratings of negative interpretations of bodily sensations, all of which decreased more in CBT. CONCLUSIONS: CBT is the preferred treatment for panic disorder with agoraphobia compared to IPT. Mechanisms of change should be investigated further, along with long-term outcomes.