Background: Neoadjuvant treatment for resectable pancreatic cancer (PDAC) is increasing in acceptability, but a standard regimen has yet to be established. The modified FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen often requires dose modifications, delays and growth factor support due to toxicity. Liposomal irinotecan injection (Nal-IRI) is FDA-approved with a well-tolerated safety profile in relapsed, refractory mPDAC. This current study substitutes Nal-IRI for traditional irinotecan in the mFOLFIRINOX regimen (NALIRIFOX) and aims to demonstrate safe neoadjuvant delivery. NALIRIFOX is currently under review by the FDA for frontline mPDAC. Methods: This phase 2, open-label, multicenter single-arm study enrolled adult patients (pts) with operable PDAC, resectability (borderline vs. resectable) confirmed by multiD conference, adequate organ function, and ECOG performance status (0-1). Pts received NALIRIFOX (per NAPOLI-3) every 2 wks x 4 mo followed by repeat imaging and surgical resection 4-8 wks later. Primary endpoint is the composite 30 day post-op major complication rate (hospital re-admission, death, second surgery, procedure or major complication extending hospital stay). A sample size of 25 pts will detect a 20% reduction in 1° endpoint (from 30% to 10%; 1-sided exact test; α=0.05; β=.8). Toxicity, treatment completion, R0 resection, clinical, biochemical and radiographic response rates and QOL during treatment (FACT-G) are 2° endpoints. Serial microbiota specimens have been collected for exploratory analysis. Results: From May 2019 to Feb 2023, 45 pts were enrolled from 4 centers. Median age was 63 (41-76), majority women (53%), white (89%) with borderline (n=30) or resectable (n=15) disease. All 45 pts initiated treatment with 34 proceeding to surgery and 29 completing definitive resection. Most common grade >3 AEs included non-febrile neutropenia (41%), diarrhea (30%), and anorexia (22%). Those not obtaining definitive resection had progressive disease (radiographic n=6; intra-op n=5), physician change of tx (n=2), toxicity (n=2; CMV colitis and TPN requirement/sepsis) or consent withdraw (n=1). Three (10%) pts had a post-op major complication (p=0.012). One pt died from post-op bleeding complications. Resections included both borderline (n=15) and resectable (n=14) initial disease with overall R0 resection rate of 89%. Conclusions: Neoadjuvant NALIRIFOX was safe, having met the primary study objective, with reasonable rates of treatment completion and surgical outcomes for this relatively high-risk group of pts. Additional analyses are ongoing and will be reported at the meeting. Clinical trial information: NCT03483038.