Although theoretical explanations for comorbidity in panic disorder (PD) abound in the literature, the complex clinical challenges of these patients have been neglected, especially where panic, obsessive-compulsive and 'soft' bipolar (e.g., hypomanic, cyclothymic and hyperthymic) conditions might co-exist. The aim of the present study has been to systematically explore the spectrum of intra-episodic and longitudinal comorbidity of 140 DSM-III-R PD patients--67.1% of whom concomitantly met the criteria for Agoraphobia--and who were consecutively admitted to the ambulatory service of the Psychiatric Clinic of the University of Pisa over a 2-year period. Comorbidity with strictly defined anxiety disorders--i.e., not explained as mere symptomatic extensions of PD--was relatively uncommon, and included Simple Phobia (10.7%), Social Phobia (6.4%), Generalized Anxiety Disorder (3.6%), and Obsessive-Compulsive Disorder (4.2%). Comorbidity with Major Depression--strictly limited to the melancholic subtype--occurred in 22.9%. Comorbidity with Bipolar Disorders included 2.1% with mania, 5% with hypomania, as well as 6.4% with cyclothymia, for a total of 13.5%; an additional 34.3% of PD patients met the criteria for hyperthymic temperament. We submit that such comorbid patterns are at the root of unwieldy clinical constructs like 'atypical depression' and 'borderline personality'. The relationship of panic disorder to other anxious-phobic and depressive states has been known for some time. Our data extend this relationship to soft bipolar disorders. Studies from other centers are needed to verify that the proposed new link is not merely due to referral bias to a tertiary university setting.