Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, and epidemiological studies have suggested positive associations with iron and red meat intake. Rare mutations in genes involved in the hepcidin-regulating pathway are known to cause iron overload and hemochromatosis. We hypothesize that the hepcidin-regulating pathway as characterized by common variants from genome-wide association studies will be associated with PDAC. Methods: We conducted a large pathway-based meta-analysis of the hepcidin-regulating genes using the summary based adaptive rank truncated product (sARTP) method in 9,253 PDAC cases and 12,525 controls of European descent from the Pancreatic Cancer Cohort (PanScan) and the Pancreatic Cancer Case-Control (PANC4) consortia. Our analysis included 11 hepcidin-regulating genes (BMP2, BMP6, FTH1, FTL, HAMP, HFE, HJV, NRF2, SLC40A1, TFR1, TFR2) and adjacent genomic regions (20 kb upstream and downstream) with a total of 412 single-nucleotide polymorphisms (SNPs). We also conducted the sARTP with four iron status biomarkers (serum iron, transferrin, transferrin saturation, and ferritin, n = 23,986) using summary statistics from previous GWAS studies (Benyamin, et al. 2014) to examine if the hepcidin-regulating genes were also associated with these iron traits. The sARTP method combines SNP-level associations across variants in a gene or a pathway. Signals from up to five of the most associated SNPs for each gene studied were accumulated. Results: The hepcidin-regulating pathway was significantly associated with PDAC (P-value = 0.002) with the HJV, TFR2, and TFR1 genes contributing the most to the association (gene level P-values = 0.001, 0.014, and 0.019, respectively). The pathway associations were more significant in women than men. This pathway was also significantly associated with the four biomarkers of iron metabolism (P-values <1.5 × 10–7). Conclusions: Our results support that genetic susceptibility related to the hepcidin-regulating pathway is associated with PDAC and a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate the modifying effect of iron-rich foods and genetic susceptibility of this pathway and PDAC risk.