Background <p>Neoadjuvant therapy is recommended for treating resectable pancreatic ductal adenocarcinoma (PDAC); however, its appropriate use in patients with resectable PDAC remains debatable.</p> Objective <p>This study aimed to identify independent poor prognostic factors and evaluate the clinical significance of neoadjuvant therapy in patients with resectable PDAC.</p> Methods <p>We retrospectively reviewed consecutive patients diagnosed with resectable PDAC at our institute between January 2003 and December 2022. We analyzed poor prognostic factors at the time of diagnosis in patients who underwent upfront surgery using the Cox proportional hazards model for overall survival (OS). The prognostic score was calculated by adding the individual prognostic factor scores.</p> Results <p>Overall, 359 patients were included in this study, with 308 patients undergoing upfront surgery and the remaining 51 patients receiving neoadjuvant therapy. The R0 resection rate was significantly higher in the neoadjuvant therapy group (70.6%) than in the upfront surgery group (64.0%). Multivariate analysis in the upfront surgery group revealed the following independent poor prognostic factors: tumor size ≥&#xa0;35&#xa0;mm, serum albumin level ≤&#xa0;.5&#xa0;g/dL, neutrophil-to-lymphocyte ratio ≥&#xa0;3.5, carbohydrate antigen 19-9 level ≥&#xa0;250&#xa0;U/mL, and Duke pancreatic monoclonal antigen type 2 level ≥&#xa0;750&#xa0;U/mL. Among patients with prognostic scores of 0–1 (<i>n</i>&#xa0;=&#xa0;263), the intention-to-treat OS did not significantly differ between the neoadjuvant therapy and upfront surgery groups. Among those patients with a prognostic score of ≥&#xa0;2 (<i>n</i>&#xa0;=&#xa0;96), the neoadjuvant therapy group had significantly longer intention-to-treat OS than the upfront surgery group.</p> Conclusions <p>Prognostic score-based stratification can help identify patients who could benefit from neoadjuvant therapy.</p>