Background: The role of multiagent chemotherapy (MAC) has not been prospectively investigated in LAPC and data are extrapolated from randomized trials in patients with metastatic disease. Data regarding the use of chemoradiation (CRT) for LAPC is mixed and similarly there is no prospective data investigating its use after MAC. Herein, we investigate clinical outcomes associated with the use of MAC and CRT. Methods: The National Cancer Database (NCDB) was utilized to identify LAPC patients treated with single agent chemotherapy (SAC), MAC, surgery, and/or CRT. Univariate (UVA) and multivariate (MVA) Cox regression were performed to identify the impact of MAC and CRT on surgical resection and median overall survival (mOS) rates. Results: From 2004-2014, a total of 10139 patients were identified. The median age was 66 years (range 22-90) with median follow up of 49 months (46-52 months); 49.9% were male and 50.1% female. All patients had clinical stage 3/T4 disease irrespective of nodal metastases. All patients who received post-op RT were excluded. Surgical resection was performed in 506 (5%) patients. Median OS rates for patients who received SAC vs. MAC was 9.8 months vs 13.7 months (p < 0.001), respectively. Median OS rates for patients who received SAC/MAC vs. SAC/MAC+CRT was 9.9 months vs. 12.9 months (p < 0.001), respectively. Odds ratio for undergoing surgical resection in patients receiving MAC vs. MAC+RT was not significant. Of the 5% of patients who underwent resection after neoadjuvant therapy, mOS for those who received MAC vs. MAC+RT were 19.4 months and 25.6 months (p = 0.001), respectively. Conclusions: Median OS was improved in patients receiving MAC versus SAC. The use of CRT after chemotherapy led to increased mOS compared to chemotherapy alone. In all patients undergoing surgical resection, the addition of neoadjuvant CRT after MAC led to improved mOS rates. Treatment with MAC followed by CRT should be utilized for all patients with LAPC.