Cyclooxygenase-2 (COX-2) plays an important role in Cholangiocarcinoma (CCA). Therefore, targeting COX-2 alone or in combination with other therapeutic agents may be a potential new effective treatment for patients with CCA. This study aimed to investigate whether Interleukin-6 (IL-6) receptor antibody could enhance the inhibitory effects of NS-398, a selective COX-2 inhibitor, on CCA cell proliferation and invasion. Human extra-hepatic CCA cell line QBC939 was used. Cell proliferation and invasion was examined by CCK-8 assay and transwell assay, respectively. The levels of Prostaglandin E2 (PGE2) and IL6 in the supernatant of QBC939 cells were measured by ELISA. The administration of NS-398 and/or IL-6R antibody markedly decreased the production of PGE2 and IL6 in QBC939 cells, and inhibited the proliferation and invasion of QBC939 cells. The combination of both NS-398 and IL-6R antibody was more potent to inhibit the production of PGE2 and IL6, as well as the proliferation and invasion of QBC939 cells than either agent alone. Moreover, the inhibition of QBC939 cell invasion by NS-398 and IL-6R antibody was abrogated by pre-treatment with PGE2. In conclusion, NS-398 and IL-6R antibody have synergistic anti-tumor effect on CCA cells. Our findings provide a rationale for the development of COX-2 and IL6 based combination therapy for effective treatment of CCA patients with poor prognosis.