1 Endothelin (ET) receptor antagonists are cardioprotective during myocardial ischaemia and reperfusion through a nitric oxide (NO)-dependent mechanism. The aim of the present study was to investigate whether the ET receptor antagonist, bosentan, is cardioprotective in atherosclerotic mice. 2 Buffer-perfused hearts from apolipoprotein E/LDL receptor double knockout (KO) and wild-type (WT) mice were subjected to global ischaemia and reperfusion. 3 Following reperfusion, the recovery of rate-pressure product (RPP; left ventricular developed pressure (LVDP) Â heart rate) was equally impaired in WT and KO mice given vehicle (3478 and 2979%, respectively). The ET A /ET B receptor antagonist bosentan (10 mmol l À1 ) improved recoveries to 57710% in WT and to 68710% in KO mice (Po0.01). Similar effects were observed for the recovery of left ventricular end-diastolic pressure (LVEDP), developed pressure and dP/dt. 4 Bosentan improved the recovery of coronary flow in both KO and WT mice. Recovery of coronary flow was significantly higher in the KO mice given bosentan (135715%) than in the WT group (111712%; Po0.01). ET-1 (1 nmol l À1 ) impaired recovery of coronary flow in both WT and KO mice though this effect was more pronounced in the KO mice (Po0.01). 5 Coronary outflow of NO during reperfusion was enhanced in both KO and WT mice following bosentan administration. 6 The ET A /ET B receptor antagonist bosentan protects the atherosclerotic mouse heart from ischaemia/reperfusion injury. The observation that ET receptor blockade and stimulation have a greater effect on coronary flow in atherosclerotic hearts indicates an increased activation of the ET system in atherosclerotic coronary arteries.