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Patients who exhibit high systemic inflammation after cardiac surgery may benefit most from pre-emptive anti-inflammatory treatments. In this secondary analysis (n = 813) of the randomised, double-blind Intraoperative High-Dose Dexamethasone for Cardiac Surgery trial, we set out to develop an inflammation risk prediction model and assess whether patients at higher risk benefit from a single intraoperative dose of dexamethasone (1 mg/kg).