<jats:sec> <jats:title>Objective:</jats:title> <jats:p>To determine the associations of pancreatobiliary maljunction (PBM) in the West.</jats:p> </jats:sec> <jats:sec> <jats:title>Background:</jats:title> <jats:p>PBM (anomalous union of common bile duct and pancreatic duct) is mostly regarded as an Asian-only disorder, with 200X risk of gallbladder cancer (GBc), attributed to reflux of pancreatic enzymes. Methods: Radiologic images of 840 patients in the US who underwent pancreatobiliary resections were reviewed for PBM and contrasted with 171 GBC cases from Japan.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>Eight % of the US GBCs (24/300) had PBM (similar to Japan; 15/ 171, 8.8%), in addition to 1/42 bile duct carcinomas and 5/33 choledochal cysts. None of the 30 PBM cases from the US had been diagnosed as PBM in the original work-up. PBM was not found in other pancreatobiliary disorders. Clinicopathologic features of the 39 PBM-associated GBCs (US:24, Japan:15) were similar; however, comparison with non-PBM GBCs revealed that they occurred predominantly in females (F/M = 3); at younger (<50-year-old) age (21% vs 6.5% in non-PBM GBCs; <jats:italic toggle="yes">P =</jats:italic> 0.01); were uncommonly associated with gallstones (14% vs 58%; <jats:italic toggle="yes">P <</jats:italic> 0.001); had higher rate of tumor-infiltrating lymphocytes (69% vs 44%; <jats:italic toggle="yes">P =</jats:italic> 0.04); arose more often through adenoma-carcinoma sequence (31% vs 12%; <jats:italic toggle="yes">P =</jats:italic> 0.02); and had a higher proportion of nonconventional carcinomas (21% vs 7%; <jats:italic toggle="yes">P =</jats:italic> 0.03). Conclusions: PBM accounts for 8% of GBCs also in the West but is typically undiagnosed. PBM-GBCs tend to manifest in younger age and often through adenoma-carcinoma sequence, leading to unusual carcinoma types. If PBM is encountered, cholecystectomy and surveillance of bile ducts is warranted. PBM-associated GBCs offer an invaluable model for variant anatomy-induced chemical (reflux-related) carcinogenesis.</jats:p> </jats:sec>