Background: This research seeks to assess the immunohistochemical (IHC) expression of Mothers against decapentaplegic homolog 4 (SMAD4) in pancreatic ductal adenocarcinoma (PDAC), explore its association with Human Epidermal Growth Factor Receptor 2 (HER2) expression, and to assess its relation to different PDAC prognostic clinico-pathological variables. The association of SMAD4 and HER2 IHC expression with patients' disease-free survival (DFS) and overall survival (OS) is also evaluated. Methods: This retrospective cohort research had 83 patients who were diagnosed with primary PDAC from surgical resection specimens at the Gastrointestinal Surgery Center (GISC), Faculty of Medicine, Mansoura University, Egypt. SMAD4 and HER2 expression were evaluated by immunohistochemistry (IHC) on PDAC tumor samples. Statistical analysis was carried out with the SPSS version 20.0 to assess significant associations. Results: SMAD4 was aberrantly expressed in 51.8% of PDACs, while only 8.4% of them were positive for HER2 (score +3). There was a statistically substantial connection between SMAD4 expression and the following variables: tumor site (p=0.05), tumor size (p=0.042), pancreatic safety (PS) margin infiltration (p=0.028) and the presence of lymphovascular invasion (LVI) (p=0.017), and `statistically significant associations between HER2 expression and the presence of LVI (p=0.03) and TNM stage (p=0.049). No substantial association was identified between SMAD4 and HER2. SMAD4 loss was connected with shorter DFS and OS, but with no statistical significance. Conclusion: SMAD4 loss is associated with a poor prognosis in PDAC patients. SMAD4 and HER2 status could affect the treatment strategies in PDAC patients.