Background: We conducted a single center safety and feasibility trial to investigate feasibility and antitumor activity of sequential FOLFIRINOX or Gemcitabine-nab Paclitaxel (GnP)and Stereotactic Body Radiotherapy (SBRT) in patients with locally advanced pancreatic cancers (LAPC). Methods: Patients with biopsy proven LAPC treated between June 2017 and August 2020 were included. Patients received two months of neo-adjuvant chemotherapy with 4 cycles of FOLFIRINOX or two cycles of GnP followed by SBRT (5 fractions/6.6Gy), total 33gy over 5 days, if no tumor progression after the initial chemotherapy was observed. Patients were reassessed for resectability after SBRT. If unresectable, they were continued on systemic therapy. Primary outcome was safety measured by proportion of grade 3/4 adverse effects. The study is registered with, and is completed. Results: Twenty-five patients enrolled were treated with FOLFIRINOX (n = 16) and GnP (n = 9). Seven (28%) patients did not receive SBRT, due to disease progression (n = 6) after initial systemic therapy, and patients’ preference (n = 1). Eighteen (72%) patients received the SBRT. Thirty-five grade 3 or 4 adverse events were observed with FOLFIRINOX and twenty-five with GnP. No grade 3 or 4 adverse events after SBRT. SBRT was administered within two weeks (median 9 days) after completion of neoadjuvant therapy. Five (27%) patients underwent a resection, all resulting in a complete (R0) resection. The patients who underwent SBRT, the Median overall survival (OS) was 28.39 95%CI (26.45 46.75) and progression free survival was 26.45 95%CI 17.25 46.7. The one-year OS and PFS were 78% (95% CI: 52%-93%) and 67% (95% CI: 41%-87%), respectively. Conclusions: Neoadjuvant FOLFIRINOX or GnP followed by SBRT in patients with LAPC is feasible and shows antitumor activity. There were no safety concerns or treatment delays with incorporation of SBRT. Clinical trial information: NCT03600623.