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3570 Background: Patients with multiple colorectal liver metastases (CLM) involving all the hepatic segments are currently not eligible for potentially curative liver surgery. Transplantation is a promising alternative but graft shortage and stringent selection criteria limit its accessibility. Owing to the improving efficacy of chemotherapy, the impossibility to resect all the initial metastatic sites could lead to revisit the role of optimal cytoreductive liver surgery (CLS) aiming to treat by resection ± radiofrequency, all the macroscopic residual tumors after a good response to chemotherapy. Although validated for ovarian cancer and peritoneal carcinomatosis, this strategy remains unexplored in CLM. Our objective was to evaluate the outcome of this strategy in patients with definitively unresectable CLM. Methods: Within a prospective monocentric study, we enrolled for debulking surgery, between 2017 and 2021, all consecutive patients with multinodular unresectable CLM involving all segments on initial imaging and consequently ineligible for a curative surgery either after a one or two-stage hepatectomy. These patients should have a strong response to chemotherapy ( > 50 % on RECIST criteria) for at least a 3-month period and no or limited extrahepatic disease, to be included. End-points of the analysis were overall and disease-free survival at 3 years. Results: Among 26 patients considered for this strategy, optimal CLS could be achieved in 21 patients after a median interval of 10 months from CLM diagnosis. The median number of lesions was 11 (7 - 26) on initial imaging. Four patients (19%) had synchronous lung metastases. Liver-first strategy was undertaken in 19 patients (90%). Postoperative complications (Grade ≥ III) occured in 5 patients (24%). One patient died within 90-day after operation from intra-abdominal hemorrage while on anticoagulation therapy. After a median follow-up of 25 months from hepatectomy, the 3-year OS rates was 85%. Median survival was not reached at the time of the analysis. Of the 4 (19%) patients with complete pathological response on the liver specimen, 3 developed recurrence. A total of 17 patients (81%) developed recurrence after a median time of 10,5 months from hepatectomy. Among them, repeat hepatectomy could be undertaken in four patients. The survival time to surgical failure (recurrence untreatable with curative intent) was 32% and 16% at 2 and 3 years. At last follow-up, seven patients (33%) are alive and recurrence-free. Conclusions: The promising results of this prospective series suggest that CLS may be worthy in patients with diffuse CLM non curatively treatable by surgery but responding well to chemotherapy. This strategy should however be reserved to hyperselected patients, super responders, eligible for an optimal resection of all the macroscopic residual tumors, and confimed by other expert centers, to be definitively validated.