Background: Upfront surgery followed by adjuvant therapy is the standard treatment for patients with rPDAC. However, the risk of positive surgical margins, the poor recovery after surgery that often impairs postoperative treatment, and the high risk of relapse might limit the overall outcome of this strategy. This trial assessed the safety and the activity of liposomal irinotecan 50 mg/m² + 5-FU 2400 mg/m² + LV 400 mg/m² + oxaliplatin 60 mg/m² (NALIRIFOX) in the perioperative treatment of patients with rPDAC. Methods: nITRO is an investigator-initiated, Simon’s two-stages, single arm phase 2 study. Eligible patients had newly diagnosed rPDAC with <180° interface with major veins’ wall and a Karnofsky status ≥60. Patients received a perioperative treatment of 3 cycles before and 3 cycles after resection with NALIRIFOX, d1 and 15 of a 28 days cycle. The primary endpoint was the proportion of patients undergoing an R0 resection. Results: Between April 2018 and May 2022, 168 patients were referred by surgical units as potentially eligible for upfront resection. These patients were prescreened by CT and MRI scans within 4 weeks before treatment and 60 showed a rapid progression to a locally advanced or metastatic disease. One was not eligible because of heart failure. Among 107 patients who were enrolled and began preoperative treatment, 86 (80.4%) received all the 3 planned preoperative cycles. One patient (0.9%) obtained a radiological complete response, 22 (20.6%) a partial response, and 68 (63.6%) a stable disease, accounting for a disease control rate of 85.0%. Nine patients discontinued because of treatment related or unrelated adverse events. Seven patients had a radiological, and 2 a clinical progression. Two patients were defined as not resectable at surgical reevaluation. Most common adverse events of grade ≥3 during preoperative treatment included neutropenia (13.0%), diarrhea (9.4%) cholangitis (6.6%), mucositis (5.6%) and hypokaliemia (5.6%). One patient died for treatment-related neutropenia and sepsis. Thus, 87 (81.2%) patients underwent surgical exploration, 11 (12.6%) of them had intraoperative evidence of unresectable or metastatic disease, and 1 died for surgical complications. Among the 75 patients who underwent resection, 49 achieved an R0 resection accounting for a rate of 65.3%, largely exceeding the alternative hypothesis of 55%. Median disease-free and overall survival of resected patients were 31.3 (95% CI 17.0-45.6) and 44.9 months (95% CI 33.1-56.8), respectively. Conclusions: NALIRIFOX was manageable and active for patients with rPDAC. Perioperative NALIRIFOX allows to select those patients who may benefit from resection to the largest extent. Perioperative NALIRIFOX deserves further investigation in randomized trials comparing it with standard upfront surgery followed by adjuvant therapy. Clinical trial information: NCT03528785.