Objective: The purpose of this study was to investigate the possibility of a differential sensitivity to CO2 in patients diagnosed with panic disorder subtypes that were defined by the presence of prominent respiratory symptoms. Method: The authors used a 35% CO2 and 65% O-2 mixture as a challenge agent. Fifty-one unmedicated subjects with DSM-III-R panic disorder, who were divided into respiratory (N=28) and nonrespiratory (N=23) subtypes by their symptom profiles, underwent a CO2 challenge procedure. Patients in the two groups were compared with regard to physiological and psychological measures, pulmonary function tests, panic rates, and smoking habits. Results: The patients in the respiratory group were significantly more sensitive to CO2 than were the patients in the nonrespiratory group. The respiratory group also had higher scores on the Panic and Agoraphobia Scale and had a longer duration of illness; both of these factors can be indicators of illness severity. In addition, the respiratory group's higher cigarette consumption (mean=12.46 package-years, SD=2.49) may have been a contributory factor not only for illness severity but also for the pathogenesis of panic disorder. Conclusions: The CO2 challenge procedure appears to be a good dissection tool in the understanding of different subtypes of panic disorder. Moreover, there may be a more specific association with prominent respiratory symptom subtype and CO2 hypersensitivity