Panic disorder (PD) has been hypothesized to be a heterogeneous entity, with distinct clinical subgroups. The presence of depersonalization during panic attacks may distinguish a specific subgroup of PD. We sought to analyze the differential features of a subgroup of PD patients with depersonalization. A total of 274 patients with PD were assessed and divided into 2 groups according to the presence or absence of depersonalization. The Structured Clinical Interview for DSM-III-R (SCID-UP-R) was used to assess PD and comorbid disorders. The clinical scales administered included the Hamilton Anxiety and Depression Rating Scale (HARS and HDRS), the Marks and Mathews Fears and Phobia Scale, Panic-Associated Symptom Scale (PASS), and a panic attack symptoms inventory. A total of 66 patients (24.1%) exhibited depersonalization during the attacks. Patients with depersonalization appeared to be younger and had an earlier age at onset. PD was more severe in the depersonalization group (greater number of attacks, worse level of functioning, and higher scores on most self-rating scales). Also, depersonalization patients showed more comorbidity with specific phobia. Our results support the view that PD with depersonalization may be considered a distinct and more severe subcategory of PD.