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Background: Genetic polymorphisms of molecules are known to cause individual differences in the therapeutic efficacy of anticancer drugs. However, to date, germline mutations (but not somatic mutations) for anticancer drugs have not been adequately studied. The objective of this study was to investigate the association between germline polymorphisms of gemcitabine metabolic and transporter genes with carbohydrate antigen 19‐9 (CA 19‐9) response (decrease ≥50% from the pretreatment level at 8 weeks) and overall survival (OS) in patients with metastatic pancreatic cancer who receive gemcitabine‐based chemotherapy. Methods: This multicenter, prospective, observational study enrolled patients with metastatic pancreatic cancer patients who were receiving gemcitabine monotherapy or gemcitabine plus nanoparticle albumin‐bound paclitaxel combination chemotherapy. Thirteen polymorphisms that may be involved in gemcitabine responsiveness were genotyped, and univariate and multivariate logistic regression analyses were used to determine the association of these genotypes with CA 19‐9 response and OS. The significance level was set at 5%. Results: In total, 180 patients from 11 hospitals in Japan were registered, and 159 patients whose CA 19‐9 response could be assessed were included in the final analysis. Patients who had a CA 19‐9 response had significantly longer OS (372 vs. 241 days; p =.007). RRM1 2464A>G and RRM2 175T>G polymorphisms suggested a weak association with CA 19‐9 response and OS, but it was not statistically significant. COX‐2 −765G>C polymorphism did not significantly correlate with CA 19‐9 response but was significantly associated with OS (hazard ratio, 2.031; p =.019). Conclusions: Genetic polymorphisms from the pharmacokinetics of gemcitabine did not indicate a significant association with efficacy, but COX‐2 polymorphisms involved in tumor cell proliferation might affect OS. This study investigated the association between germline polymorphisms of gemcitabine metabolic and transporter genes and carbohydrate 19‐9 response and overall survival in patients with metastatic pancreatic cancer who were receiving gemcitabine‐based chemotherapy. Germline polymorphisms of the metabolic pathway and transporter genes in gemcitabine were not significantly associated with efficacy, but COX‐2 polymorphisms were associated with overall survival. [ABSTRACT FROM AUTHOR]