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Simple Summary: Patients with pancreatic ductal adenocarcinoma (PDAC) are increasingly receiving neoadjuvant therapy (NAT) with the aim of improving patient care. However, complete tumor regression remains rare, and there is a dire need for biomarkers that can predict responses to NAT. SMAD4 is a protein that is inactivated in about half of PDACs and has been described as associated with metastasis and resistance to therapy. The aim of our study is to investigate whether SMAD4 status is a prognostic and predictive factor in patients with pancreatic cancer receiving NAT. In our cohort of patients, SMAD4 loss was associated with quicker progression and metastasis development. When patients were subgrouped depending on their type of neoadjuvant treatment, those receiving FOLFIRINOX-based NAT and presenting SMAD4-positive tumors showed the best outcome. This result suggests that SMAD4 may be a potential biomarker for patients with pancreatic cancer receiving NAT and may help improve patient care. Background: SMAD4 is inactivated in 50–55% of pancreatic ductal adenocarcinomas (PDACs). SMAD4 loss of expression has been described as a negative prognostic factor in PDAC associated with an increased rate of metastasis and resistance to therapy. However, the impact of SMAD4 inactivation in patients receiving neoadjuvant therapy (NAT) is not well characterized. The aim of our study was to investigate whether SMAD4 status is a prognostic and predictive factor in patients receiving NAT. Methods: We retrospectively analyzed 59 patients from a single center who underwent surgical resection for primary PDAC after NAT. SMAD4 nuclear expression was assessed by immunohistochemistry, and its relationship to clinicopathologic variables and survival parameters was evaluated. Interaction testing was performed between SMAD4 status and the type of NAT. Results: 49.15% of patients presented loss of SMAD4. SMAD4 loss was associated with a higher positive lymph node ratio (p = 0.03), shorter progression-free survival (PFS) (p = 0.02), and metastasis-free survival (MFS) (p = 0.02), but it was not an independent prognostic biomarker in multivariate analysis. Interaction tests demonstrated that patients with SMAD4-positive tumors receiving FOLFIRINOX-based NAT showed the best outcome. Conclusion: This study highlights the potential prognostic and predictive role of SMAD4 status in PDAC patients receiving FOLFIRINOX-based NAT. [ABSTRACT FROM AUTHOR]