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Background There is evidence that negative affect (NA) and anxiety sensitivity (AS) predict the development of anxiety disorders, particularly panic disorder (PD). The main purpose of this study was to examine whether NA and AS will also predict the clinical course of PD. Methods Participants were 136 individuals with a DSM-III-R diagnosis of PD (with or without agoraphobia) enrolled in a naturalistic and longitudinal study of anxiety disorders, the Harvard/Brown Anxiety Research Project (HARP). Participants were administered the Anxiety Sensitivity Index and the Negative Affect Scales of the Positive and Negative Affect Schedule-Expanded Form (PANAS-X-NA) and their percentage of time in PD episode was followed for 1 year after the administration of the measures. Results Multiple regression analyses indicated that AS, but not NA, was a significant predictor of percentage of time in PD episode after controlling for previous time in PD episodes, comorbid depression, other anxiety disorders, and exposure to psychopharmacological and behavioral treatments. As expected, the Physical Concerns subscale of the Anxiety Sensitivity Index had a significant independent contribution in predicting the course of the disorder. Conclusions Overall, these findings suggest that AS, as a unique construct, may be predictive of the amount of time patients are in episode of PD.