Chronic thromboembolic pulmonary hypertension is a rare and life-threatening disorder characterized by unresolved thromboemboli associated with fibrous stenosis in large proximal pulmonary arteries. Knowledge of the causing factors and pathophysiology remains incomplete. Based on our recent observation that CTEPH patients display increased plasma levels of C-reactive protein (CRP), a maker of inflammation, we aimed to investigate the role of inflammation in the pathophysiology of CTEPH and more specifically the role of CRP. First, we evaluated the morphometry and cellular content of proximal arterial lesions of CTEPH patients and analysed the pattern of systemic inflammatory mediators. We evidenced the presence of neointima, thrombotic, recanalized and atherosclerotic lesions. An accumulation and infiltration of inflammatory cells and correlations between local accumulation of inflammatory cells and circulating inflammatory markers suggests a link between systemic and local inflammation, which could contribute to the progression of CTEPH. Second, we extensively characterized EC and SMC from proximal pulmonary arteries from CTEPH patients. We observed a proliferative phenotype of SMC, indicated by a down-regualtion of desmin, a marker of late differentiation, and modified proliferative and/or migratory responses of SMC and EC in vitro. This suggests that SMC and EC could contribute to proximal vascular remodeling in CTEPH. Next, we found that CRP was able to enhance SMC mitogenic activity, inflammatory cell adhesion to EC, secretion of ET-1 and vWF by EC from CTEPH patients and therefore might contribute to vascular remodeling, thrombosis and endothelial dysfunction. We also found a local expression of CRP in EC and SMC within the pulmonary vascular wall. The scavenger receptor LOX-1 was overexpressed in pulmonary arteries of CTEPH patients. We found a differential expression of NFκB pathway-related genes in CRP-activated CTEPH-EC and an inhibition of NFκB pathway in cell culture assays impaired CRP-induced EC adhesive capacities and dysfunction, suggesting that the NFκB pathway could mediate the effects of CRP on CTEPH pulmonary vascular cells. Finally, we showed that the ET-1 receptor antagonists bosentan and sitaxsentan dose-dependantly inhibit the mitogenic activity of proximal CTEPH-, PH- and donor-SMC. We can conclude that using different approaches, including measurement of plasma inflammatory mediators, primary human cell culture, molecular biology and immunofluorescence, we have evidenced that inflammation could play a key role in the pathophysiology of CTEPH.