BACKGROUND: Paralytic ileus is a major surrounding after cardiac surgery and worsens patients' prognosis. METHODS: We conducted a single-centre, randomized, double-blind, placebo-controlled phase 3 study. We enrolled patients over 18 years old who underwent non-urgent cardiac surgery. Eligible patients were randomly allocated to Naloxegol or matching placebo in an equal ratio. The participants were randomly assigned to one of the following groups: (1) Naloxegol 12,5 mg 2 hours before index surgery, and then Naloxegol 25 mg once daily, or (2) matching placebo. Naloxegol or placebo was administered for up to 5 days and permanently stopped if the patient had transit recovery. The primary endpoint was the time of postoperative gastrointestinal transit recovery after the index cardiac surgery, defined as the time in hours between the anaesthetic induction and the emission of the first significant stool. RESULTS: Between October 14, 2020, and January 28, 2022, 299 participants were included in modified intention-to-treat efficacy analyses (151 in the Naloxegol group and 148 in placebo). The mean age was 62 ± 10.1 years old, 81.6% were male, 53.8% had hypertension, 20.7% had diabetes mellitus, and the median body mass index was 25.9 (IQR 23.7-29.4) kg/m CONCLUSIONS: Naloxegol was not found to be effective in improving the transit time recovery after elective cardiac surgery. The trial was registered on clinicaltrials.gov (NCT04433390) on June 16, 2020.