Abstract Introduction/Objective The periampullary region is histologically complex owing to the confluence of three different kinds of epithelia (duodenal, pancreatic, biliary) harbouring four types of cancers. Although anatomical proximity warrants a common surgical approach, overall survival depends largely on the type of surgical indication. Malignant epithelial tumors are the predominant indications, accompanied by a myriad of benign tumors and tumor-like lesions. We reviewed our archival pancreaticoduodenectomies to analyze the spectrum of these lesions. Methods All pancreaticoduodenectomy specimens received in Department of Pathology, from 2005–2019 (15 years) were analyzed for histological spectrum. Results A total of 786 pancreaticoduodenectomies were received with an overall M:F= 2.3:1 and age range 17–91 years. Of these, 94.4% were neoplastic (742 cases) and 5.6% were non-neoplastic. Benign neoplastic lesions (19 cases, 2.4%) included adenomyoma (7 cases, 0.9%), solid-cystic pseudopapillary tumor of pancreas (5 cases, 0.6%), intraductal papillary mucinous neoplasm (2 cases, 0.3%) and one case each of serous cystadenoma, mucinous cystic neoplasm, dermoid cyst, gangliocytic paraganglioma and Peutz-Jeghers polyp. Ampullary adenocarcinoma was the predominant malignant epithelial lesion (609 cases, 77.5%) followed by distal CBD cancer (43 cases, 5.5%), pancreatic head cancer (20 cases, 2.5%), neuroendocrine tumors (22 cases, 2.8%), carcinoma gallbladder (5 cases, 0.6%) and one case of ampullary adenosquamous carcinoma (0.1%). Non-epithelial tumors included 9 cases of GIST (1.1%), 3 of carcinosarcoma and one case each of leiomyosarcoma and lymphoma. Non-neoplastic lesions (3.2%) included 22 cases of chronic pancreatitis and one case each of xanthogranulomatous pancreatitis, lymphoplasmacytic slcerosing pancreatitis and xanthogranulomatous cholecystitis. Ectopic pancreas was rare (2 cases, 0.3%) and 16 cases (2%) were negative for any specific pathology. Conclusion This is the largest data on histological spectrum of pancreaticoduodenectomies from India. The malignant lesions form the major bulk (94%), however benign lesions also account for a substantial percentage of surgical indications. Among malignant lesions, ampullary cancers outreach far above pancreatic cancers in the Indian subcontinent.