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Introduction Impairment of the hypothalamic–pituitary–adrenal axis during critical illness, called Critical Illness-Related Corticosteroid Insufficiency (CIRCI), is frequent. There is no standard treatment for CIRCI. This trial aims to determine whether, through biomarker enrichment using CIRCI criteria, hydrocortisone and fludrocortisone, compared with placebo, improve organ dysfunction-free survival in critically ill patients.Methods and analysis French multicentre, placebo-controlled, double-blind superiority trial that will randomly assign adults with CIRCI to receive a 7-day course of hydrocortisone and fludrocortisone or their placebo. Randomisation (1:1) will be stratified by centre and presence or absence of acute respiratory distress syndrome. The primary outcome, number of ventilator-free and vasopressor-free days within 30 days (deaths assigned zero days) after randomisation, will be analysed using a Bayesian model. Patients who do not suffer from CIRCI will be followed up for 90 days.Ethics and dissemination The protocol was approved by the Ethics Committee (Comité de Protection des Personnes, Ouest I, France no 2021T1-11) on 23 September 2021. Trial results will be disseminated at scientific conferences and results will be published in peer-reviewed journals.Trial registration number NCT04404400.