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Background Primary adenocarcinomas removed by pancreatoduodenectomy originate from the duodenum (DC), ampulla (AC), distal bile duct (DBC), or pancreas (PC). Pathobiology, staging, survival, and adjuvant chemotherapy vary among these cancers. The proximity of the structures of possible origin renders it difficult to obtain a correct diagnosis, which might lead to inconsistencies in reported data and inappropriate adjuvant treatment. Methods Records of 207 patients undergoing pancreatoduodenectomy (1998–2009) for periampullary adenocarcinoma were reviewed. Routine histopathology reports of tumour origin performed by multiple pathologists were independently re-evaluated based on predetermined criteria by two experienced pancreatic pathologists. Results Slide review changed the diagnosis in 55 (27%) patients. After reclassification, final distribution was 29 (14%) DC, 52 (25%) AC, 57 (28%) DBC, and 69 (33%) PC. The diagnosis was revised in 4 (14%) DC, 7 (17%) AC, 30 (53%) DBC and 14 (19%) PC. The underestimation of DBC during routine histopathology was caused by misinterpretation of DBC either PC or AC. Misclassification of PC was mainly due to erroneous diagnosis of AC. Reassignment of tumour origin caused no significant changes in survival within cancer type, but resulted in a significant difference in survival between DBC and PC (p = 0.004). Conclusion Specialist slide review resulted in reassignment of tumour origin in 27% of periampullary adenocarcinomas. Distal bile duct cancer was found to be most frequently misdiagnosed (53%). Correct diagnosis of tumour origin is crucial for data quality, appropriate adjuvant therapy, and patient inclusion in clinical trials.