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Background Pembrolizumab has shown promising results for patients with programmed cell death ligand-1 (PD-L1)-positive solid tumors. However, data on immunotherapy for biliary tract cancers are limited, and biomarkers to identify appropriate candidates for immunotherapy needs to be defined. Methods A total of 153 patients with advanced biliary tract cancers were included (gallbladder n = 48, distal bile duct n = 17, perihilar bile duct n = 32, intrahepatic bile duct n = 49, and ampulla of vater n = 7). Patients were screened for PD-L1 expression by a prototype immunohistochemistry assay (PharmDx). Of PD-L1-positive patients, 12 patients were treated with pembrolizumab. Treatment response was evaluated and correlated with PD-L1 immunohistochemistry, microsatellite instability (MSI) status, tumor-infiltrating lymphocytes (TIL), and CD8+ T cells density. Results 74% (113 of 153) of patients showed tumoral PD-L1 positivity at 1% cut off, and 8.5% (13 of 153) patients showed high PD-L1 expression (tumor proportion score ≧ 50). Of 122 patients with MSI status, only one patient had MSI-H tumor. Twelve patients were treated with pembrolizumab, and all treated patients received prior standard chemotherapy. Two (16.7%) patients had dramatic treatment response, and the rest showed no response. Both two responders had high PD-L1 expression (tumor proportion score ≧ 50), and high PD-L1 expression was associated with treatment response (P = 0.045) None of treated patients was MSI-H. Of two responders, one showed the highest TIL and CD8+ cells density. However, TIL and CD8+ positive cells densities were not significantly associated with treatment response. Conclusions Approximately 10% of patients with advanced biliary tract cancers revealed high PD-L1 expression, and high PD-L1 expression was associated with treatment response of pembrolizumab. MSI-H was rare in biliary tract cancers. We suggest that PD-L1 expression need to be evaluated to identify patients who would benefit from immunotherapy for advanced biliary tract cancers. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.