Summary Cardiac surgery with cardiopulmonary bypass is associated with the development of a systemic inflammatory response that can often lead to dysfunction of major organs. We hypothesised that the highly selective α2‐adrenergic agonist, dexmedetomidine, attenuates the systemic inflammatory response. Forty‐two patients were randomly assigned to receive dexmedetomidine or saline after aortic cross‐clamping). The mean (SD) levels of the nuclear protein plasma high‐mobility group box 1 increased significantly from 5.1 (2.2) ng.ml−1 during (16.6 (7.3) ng.ml−1) and after (14.3 (8.2) ng.ml−1) cardiopulmonary bypass in the saline group. In the dexmedetomidine group, the levels increased significantly only during cardiopulmonary bypass (4.0 (1.9) ng.ml−1 baseline vs 10.8 (2.7) ng.ml−1) but not after (7.4 (3.8) ng.ml−1). Dexmedetomidine infusion also suppressed the rise in mean (SD) interleukin‐6 levels after cardiopulmonary bypass (a rise of 124.5 (72.0) pg.ml−1 vs 65.3 (30.9) pg.ml−1). These suppressive effects of dexmedetomidine might be due to the inhibition of nuclear factor kappa B activation and suggest that intra‐operative dexmedetomidine may beneficially inhibit inflammatory responses associated with ischaemia‐reperfusion injury during cardiopulmonary bypass.