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Adverse neurologic outcome can be a debilitating complication after cardiac surgery. The aim of this study was to investigate the potential neuroprotective action of erythromycin, a well known antibiotic agent, regarding postoperative cognitive decline in patients undergoing cardiac surgery.Forty patients scheduled for elective coronary artery bypass grafting surgery were prospectively randomly assigned in 2 groups: the erythromycin group (n = 19) who received erythromycin at a dose of 25 mg/kg before and after surgery and the control group (n = 21) who did not receive it. All patients were monitored with near-infrared spectroscopy during the operation. Interleukin (IL) 1 and IL-6 as inflammatory markers and tau protein as a marker of brain injury were measured before and after surgery. Neurocognitive assessment was performed before surgery, on the day of discharge, and at 3 months postoperatively.Both groups were comparable in terms of demographic and clinical data. Patients who took erythromycin presented with significantly better cognitive performance before discharge and 3 months after surgery. No significant differences between the 2 groups referring to IL-1 and IL-6 values were detected. Tau serum values were lower in the erythromycin group after surgery.Erythromycin administration attenuates cerebral damage and postoperative cognitive decline after coronary artery bypass grafting surgery.The study was retrospectively registered at ClinicalTrials.gov (NCT01274754). Study start day: November 2008.