Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by thrombo-fibrotic obstruction of proximal pulmonary arteries. The cellular and molecular mechanisms underlying the pathogenesis remain incompletely understood, although we recently evidenced the potential involvement of the inflammatory marker, C-reactive protein (CRP). We aimed to investigate the intracellular mechanisms induced by CRP in proximal pulmonary arterial endothelial cells (PAEC). PAEC were isolated from vascular material obtained during pulmonary endarterectomy. RNA was extracted from CRP-stimulated PAEC and first stand cDNA was generated. A RT² profiler PCR Array was used to evaluate the expression of 84 key genes related to NFB-mediated signal transduction. CRP-induced NFB activation was studied. Effects of PDTC, an inhibitor of the NFB pathway, were investigated on CRP-induced adhesion of monocytes to PAEC, adhesion molecule expression, endothelin-1 (ET-1), interleukin-6 (IL-6) and von Willebrand factor (vWF) secretion. Compared to non-stimulated PAEC, serotonin receptor 2B was down-regulated by 25%, inhibitor of NFB kinase subunit epsilon (IKBKE) by 30%, and toll-like receptor 4 and 6 by 18% and 39%, respectively, in CRP-stimulated PAEC. The transcription factor FOS was 3-fold up-regulated. CRP induced RelA/NFBp65 phosphorylation. PDTC dose-dependently inhibited the adhesion of monocytes to CRP-stimulated PAEC. PDTC also inhibited the CRP-induced expression of ICAM-1 at the surface of PAEC. PDTC impaired the secretion of ET-1 by 18% and tended to inhibit the secretion of IL-6 by CRP-stimulated PAEC by 46%. PDTC did not inhibit the CRP-induced secretion of vWF. These results suggest an involvement of the NFB pathway in mediating different effects of CRP on proximal CTEPH-PAEC.