Tumor metabolism measured by ¹⁸F-FDG PET has a diagnostic and prognostic role in several cancers. The clinical implication of tumor metabolism in biliary tract cancer (BTC) has not been studied well. Therefore, we evaluated the prognostic value of tumor metabolism and chemotherapy-related changes in advanced BTC patients. Methods: We prospectively enrolled advanced BTC patients before the initiation of palliative chemotherapy. Using ¹⁸F-FDG PET, we assessed the baseline SUV_max and monitored the changes in SUV_max during chemotherapy. We analyzed the associations between SUV_max, and clinicopathologic factors and clinical outcomes. Results: Seventy-five patients were enrolled. All patients received gemcitabine/cisplatin as first-line chemotherapy. Primary tumor site, histologic differentiation, molecular characteristics, laboratory findings, and disease extent were associated with the metabolic characteristics. The high-metabolism group showed worse survival outcome (hazard ratio [HR] = 4.09, P = 0.001 for progression-free survival; HR = 2.61, P = 0.019 for overall survival [OS]) than the low-metabolism group. The lesser reduction of SUV_max was also associated with worse outcome (HR = 3.35, P = 0.002 for progression-free survival; HR = 1.96, P = 0.082 for OS). When both baseline tumor metabolism and its chemotherapy-related changes were considered, patients with a low metabolism and more reduction in metabolism obtained the best OS (20.7 vs. 6.2 mo, P = 0.013). Conclusion: Tumor metabolic activity and the chemotherapy-related changes in the metabolism are associated with prognosis in advanced BTC patients.