Background: Pancreatic adenocarcinoma (PDAC) carries a dismal prognosis. Neoadjuvant chemoradiation therapy (NACR) has been introduced to enhance the outcomes of patients with borderline resectable and locally advanced PDAC, however the role of radiation therapy remains largely unknown. Methods: The National Cancer Database (NCDB) was queried for patients with stage I-III PDAC who underwent surgical resection from 2004 to 2014. Patients undergoing NACR were compared to those undergoing neoadjuvant chemotherapy (NAC) alone. The association between clinical characteristics and overall survival (OS) was assessed using the Kaplan-Meier method and multivariable Cox regression model. Results: Of 3,133 patients, 2,351 (75%) patients underwent NACR and 782 (25%), NAC alone. Most patients were Caucasians (84%), treated at academic institutions (67%) and underwent pancreaticoduodenectomy (74%). Median follow-up time was 32 months (IQR, 22-50 months). Median number of lymph nodes examined (LNE) and number of positive nodes (NPN) were significantly decreased in NACR (13 vs. 16, p < 0.001 and 0 vs. 1, p < 0.001, respectively). Rates of margin positivity, median OS and 5-year OS were similar between 2 groups (NACR vs. NAC: 15% vs. 17%, p = 0.545; 25.7 months (95% CI 24.4–26.7) vs. 25.1 months (95% CI: 23.9–27.5), and 20% vs. 22%, p = 0.616, respectively, Figure 1). Subgroup analysis of high-risk features (R1/R2 and N1) also showed no difference in survival outcomes. Neoadjuvant radiation was not an independent predictor associated with OS, whereas advanced age, R1/R2, T3/T4, N1, and poorly differentiated histology were independent negative prognostic factors. Conclusions: NACR is associated with lower rates of lymph node positivity, however this did not translate in survival or margin positivity benefit compared to NAC alone. The role of radiotherapy in PDAC continues to evolve, however no convincing data is currently available to advocate the widespread use of radiotherapy in the neoadjuvant setting. Further evidence with prospective clinical trials is still warranted to confirm these findings.