Background: Most patients (pts) who undergo surgical resection (SR) for pancreatic ductal adenocarcinoma (PDA) relapse and die. Adjuvant chemotherapy (CT) improves survival compared to observation in randomized trials, but median disease-free survival (DFS) and overall survival (OS) are only 13.4m and 22.1m, respectively. Multiagent CT in the metastatic setting improves DFS and OS compared to gemcitabine (G) alone. Neoadjuvant (NA) treatment of resectable PDA is a rational though unproven strategy to improve standard results. We hypothesized NA multiagent CT and chemoradiotherapy (CRT) paired with SR and adjuvant CT would be manageable and improve the OS of pts with borderline (BR)/resectable (R) PDA. Methods: This was a prospective, single arm, single institution phase II trial. Eligibility included confirmed PDA, R/BR disease, ECOG ≤ 2, and adequate organ function. NA CT (3 cycles of GTX (G 750mg/m² over 75 minutes and docetaxel 30mg/m² days (d) 4 and 11, capecitabine (C) 750mg/m² BID d1-14)) followed by CRT (IMRT 3 Gy/fraction on days 1-5 and 8-12 (30 Gy total) with C 650mg/m² BID d1-14 and oxaliplatin (O) 60mg/m² d1 and 8. Adjuvant CT was 2m of GemOx (G 1000mg/m² and O 85mg/m² d1 every 14d) and 2m of standard G. The primary objective was to estimate the OS of pts treated in this fashion. Secondary objectives included DFS, Response Rate (RR), pathologic RR, SR completion and safety. Results: 35 pts were enrolled, 16 had BR disease and 16 were clinically node positive. One pt had progression during NA CT and 32 (91%) completed NA CRT. 31 (89%) pts went to surgery, 6 had occult metastases, 2 were locally advanced and 23 had SR (74% R0 and 26% R1). Pathology demonstrated 1 pCR and 87% N0. Among 35 pts enrolled, 21 (60%) are alive with a median follow-up of 23.6m. Median OS of all 35 patients is 31.1m and mDFS is 27.6m. Of 23 pts who underwent SR, 18 remain alive with a median follow-up of 25.7m. Estimated mDFS is 35.1m with a lower 95% confidence limit of 18.9m and mOS is not reached to date. Conclusions: In this phase II study, peri-operative multiagent CT and CRT was feasible and resulted in promising DFS and OS outcomes relative to historical controls. The current results are encouraging and warrant further evaluation. Clinical trial information: NCT00609336.