Background <p>Key prognostic factors in periampullary tumors include tumor size, histopathological subtype, degree of differentiation, lymph node metastasis, perineural invasion, and lymphovascular invasion. Therefore, evaluating molecular markers alongside traditional histopathological parameters may improve the accuracy of prognostic classification.</p> Aim <p>We seek to examine how HER2/neu status relates to clinicopathological features like T-stage, N-stage, and anatomical site to better define its potential as a clinical tool for managing periampullary tumors.</p> Methods <p>This study was conducted as a retrospective, single-center analytical research involving 84 patients who underwent curative-intent pancreaticoduodenectomy at a tertiary referral center. ASA scores, histopathological type, TNM stage, tumor diameter and grade, perineural and lymphovascular invasion status, overall survival times, immunohistochemical results for HER-2/neu expression in both the resected pancreatic tissue and lymph nodes were recorded.</p> Results <p>The study included 84 patients with a mean age of 63.01 ± 11.96 years. During the follow-up period, 38.1% (<i>n</i>=32) of patients were alive, while 61.9% (<i>n</i>=52) had died. Most frequent site of origin was the pancreatic head (44%, <i>n</i>=37), followed closely by the ampulla of vater (39.3%, <i>n</i>=33). Distal common bile duct tumors accounted for 13.1% (<i>n</i>=11), and duodenal tumors for 3.6% (<i>n</i>=3). Histopathological subtypes were identified as intestinal (35.7%, <i>n</i>=30), pancreatobiliary (47.6%, <i>n</i>=40), mucinous (4.8%, <i>n</i>=4), signet ring cell (6%, <i>n</i>=5), neuroendocrine (4.8%, <i>n</i>=4), and medullary (1.2%, <i>n</i>=1).</p> Conclusion <p>HER2/neu may be utilized as a marker of aggressive local behavior and lymphatic involvement rather than a definitive prognostic factor in early-stage disease.</p>