We tested the hypothesis that patients with chronic thromboembolic pulmonary hypertension (CTEPH) deemed inoperable were more likely to respond to PAH drugs than those CTEPH deemed operable, using cardiopulmonary exercise testing (CPX). We analyzed CPX data of all CTEPH patients who were treated with PAH drugs and had undergone CPX testing pre- and post-treatment at a single Pulmonary Hypertension center between February 2009 and March 2013. Suitability for pulmonary endarterectomy (PEA) was decided at a PEA expert center. The inoperable group included 16 patients and the operable group 26 patients. There was no difference in demographics and baseline hemodynamics between the groups. Unlike the operable group, after drug treatment inoperable patients had a significantly higher peak VO2 (p<0.001), workload (p=0.002) and oxygen pulse (p<0.001). In terms of gas exchange, there was an overall net trend towards improved VE/VCO2 in the inoperable group, with an increased PaCO2 (p=0.01), suggesting reduced hyperventilation. No changes were seen in the operable patients. In conclusion, treatment with PAH drug therapies reveals important pathophysiological differences between inoperable and operable CTEPH, with significant pulmonary vascular and cardiac responses in inoperable disease. Drug effects on exercise function seen in inoperable CTEPH cannot be translated to all forms of CTEPH.