INTRODUCTION: Efforts have focused in recent decades on developing anaesthetic strategies that limit the use of morphine because of its known side effects. This study aims to compare postoperative morphine consumption between opioid-free anaesthesia (OFA) and conventional opioid-based general anaesthesia. METHODS AND ANALYSIS: Phase III, multicentre, randomised controlled study comparing morphine consumption in the immediate postoperative period (first 48 hours) between OFA and conventional general anaesthesia (CGA). The study is conducted across three French academic cancer centres, with a planned enrolment of 158 patients, randomly assigned (1:1) to the OFA and CGA. The primary outcome is morphine consumption during the first 48 hours postoperatively. ETHICS AND DISSEMINATION: The study has been approved by the National Research Ethics Committee (CPP, reference number 1-22-036/22.01675.000085) and the French National Agency for Medicines and Health Products Safety (ANSM, reference number MEDAECNAT-2022-04-0057). Written, informed consent to participate will be obtained from all participants. Results will be published in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: This trial has been registered in the Clinical Trials in the European Union database (CTIS number: 2024-513308-32-00) and in ClinicalTrials.gov (NCT05439005).