Background: Based on our previous pilot study, systemic inflammatory response syndrome is more common in off-pump compared to on-pump coronary artery bypass. Therefore, we conducted a clinical trial of dexamethasone in patients undergoing off-pump coronary artery bypass. Methods: Sixty consecutive patients undergoing off-pump coronary artery bypass were enrolled from August 2018 to January 2019 and randomized to a dexamethasone or placebo group of 30 each. Clinical outcomes were analyzed. Results: There was a lower incidence of major adverse cardiac events in the dexamethasone group compared to the placebo group (17% versus 43%, p = 0.024). Clinical outcomes in the dexamethasone group were better than those in the placebo group, in terms of duration of mechanical ventilation (p = 0.029), intensive care unit stay (p = 0.028), hospital stay (p = 0.04), and vasoactive-inotropic score (p = 0.045). There were significant differences in inflammatory markers between the two groups: interleukin-6 (p = 0.0001), procalcitonin (p = 0.0001), and C-reactive protein (p = 0.0001) were lower in the dexamethasone group. There was a significant association between the incidence of major adverse cardiac events and both interleukin-6 (p = 0.005) and procalcitonin (p = 0.007). Conclusion: Preoperative dexamethasone in patients undergoing off-pump coronary artery bypass is effective in improving clinical outcomes and controlling the postoperative inflammatory reaction. © The Author(s) 2020.