Background: Fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) has shown improved survival in metastatic pancreatic cancer, and promising results as downstaging chemotherapy in locally advanced pancreatic cancer. The efficacy of neoadjuvant FOLFIRINOX in patients with resectable pancreatic cancer is unknown. Methods: This is a randomized phase II trial with patients included from 12 Nordic centers in the period 2017-2021. Patients with resectable pancreatic head cancer were randomly assigned to receive either four neoadjuvant cycles of FOLFIRINOX followed by surgery and eight adjuvant cycles mFOLFIRINOX, or upfront surgery and adjuvant mFOLFIRINOX (12 cycles). The primary endpoint was overall survival at 18 months after date of randomization (intention-to-treat [ITT]). Overall survival was estimated with the Kaplan-Meier method, and differences between the respective treatment arms were analyzed with log rank tests. Results: In NORPACT-1, 140 patients were randomly assigned (neoadjuvant chemotherapy, n=77;upfront surgery, n=63). Median age was 66.5 years (IQR 59, 72), while 115 (82.1%) and 25 (17.9%) patients were ECOG 0 and 1, respectively. Median OS by ITT was 25.1 months [95% CI 17.2-34.9] with neoadjuvant chemotherapy and 38.5 months [95% CI 27.6-not reached] with upfront surgery (p=0.096). The proportion of patients alive at 18 months by ITT was 59.7 % [95% CI 48.9-70.7] and 73.0 % [95% CI 62.0-84.0], respectively (p=0.100). Resection rates were 81.8% (63/77) in the neoadjuvant group and 88.9% (56/63) in the upfront surgery group (p=0.342). In the neoadjuvant group 61 (79.2%) patients initiated neoadjuvant FOLFIRINOX. Completion of the four planned cycles was 60%, with dose reductions and delays in 70% and 28.3%. Per-protocol (PP) analysis of 60 patients with pancreatic ductal adenocarcinoma (PDAC) who received minimum one cycle neoadjuvant FOLFIRINOX compared with 55 patients in the upfront surgery arm who were explored showed median OS of 23.0 months [95% CI 16.2-34.9] and 34.4 months [95% CI 19.4-not reached] (p=0.158). Adjuvant chemotherapy initiation rate was 66.2% and 74.6% (p=0.282) by ITT. In resected PDAC patients the rate was 86.4% and 89.8% (p=0.593). Of 120 patients receiving at least one dose of neoadjuvant and/or adjuvant chemotherapy (safety population), 57.5% (42/73) in the neoadjuvant group and 40.4% (19/47) in the upfront surgery group experienced at least one grade ≥3 adverse event (p=0.067). In PP analysis neoadjuvant FOLFIRINOX was associated with significantly higher rate of N0 (p=0.002) and R0 resection (p=0.011). Conclusions: Neoadjuvant FOLFIRINOX did not improve OS compared with upfront surgery in resectable pancreatic head cancer. Our results do not support neoadjuvant chemotherapy as standard of care for these patients. Future trials should incorporate a biomarker-based design. Clinical trial information: NCT02919787.