BACKGROUND: Opioid-induced constipation (OIC) is a common symptom in cancer patients treated with opioids with a prevalence of up to 59%. International guidelines recommend standard laxatives such as macrogol/electrolytes and magnesium hydroxide to prevent OIC, although evidence from randomized controlled trials is largely lacking. The aim of our study is to compare magnesium hydroxide with macrogol /electrolytes in the prevention of OIC in patients with incurable cancer and to compare side-effects, tolerability and cost-effectiveness. METHODS: Our study is an open-label, randomized, multicenter study to examine if magnesium hydroxide is non-inferior to macrogol/electrolytes in the prevention of OIC. In total, 330 patients with incurable cancer, starting with opioids for pain management, will be randomized to treatment with either macrogol/electrolytes or magnesium hydroxide. The primary outcome measure is the proportion of patients with a score of < 30 on the Bowel Function Index (BFI), measured on day 14. The Rome IV criteria for constipation, side effects of and satisfaction with laxatives, pain scores, quality of life (using the EQ-5D-5L), daily use of laxatives and escape medication, and cost-effectiveness will also be assessed. DISCUSSION: In this study we aim to examine if magnesium hydroxide is non-inferior to macrogol/electrolytes in the prevention of OIC. The outcome of our study will contribute to prevention of OIC and scientific evidence of guidelines on (opioid-induced) constipation. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov: NCT05216328 and in the Dutch trial register: NTR80508. EudraCT number 2022-000408-36.