Exposing the heart to brief periods of ischaemia followed by reperfusion (ischaemic preconditioning) is a powerful tool for protecting the heart from further ischaemic insults. Understanding the mechanisms involved in this phenomenon is vital for the translation of preconditioning techniques into clinical applications. Many preconditioning studies utilize healthy heart models to evaluate the effectiveness and mechanisms of preconditioning, however it is essential to assess the effects of preconditioning protocols on the compromised or diseased heart in order to fully appreciate the potential of preconditioning to improve outcome of patients with coronary disease. When fed a high fat diet for 24 weeks, male apolipoprotein E knockout mice (apoE^-/-) develop atherosclerotic lesions in the coronary arteries and show coronary artery disease similar to that seen in humans. Previous work [1] has shown that the hearts from these mice are resistant to ischaemic insult compared to healthy apoE ^-/- hearts from mice fed a standard chow diet. The aim of this study is to evaluate the ability of the diseased apoE ^-/- heart to be protected by ischaemic preconditioning techniques. Hearts from 8 month old male apoE ^-/- mice fed a high fat diet for 24 weeks were excised and perfused in Langendorff mode with Krebs-Henseleit buffer. Following a 20 minute stabilization period, hearts were either subjected to a preconditioning protocol of 2 cycles of 5 min ischaemia and 5 min reperfusion (ischaemic preconditioned , IP), or were continually perfused for 20 min (control). Hearts were subjected to 60 minutes global ischaemia followed by 60 minutes reperfusion. Functional recovery (left ventricular developed pressure, LVDP) was assessed and creatine kinase release upon reperfusion was measured as an indicator of myocardial injury. There was no significant difference in functional recovery between control and IP hearts after 60 minutes reperfusion (% LVDP 58.9 ± 8.6 % for control vs. 64.5 ± 8.3 % for IP hearts, data are mean ± S.E. for n=6 hearts in each group, p=0.65 unpaired t-test). There was also no difference in myocardial injury as determined by creatine kinase release into the coronary effluent upon reperfusion. The results presented here indicate that apoE ^-/- hearts with coronary artery disease are resistant to further cardioprotective effects of ischaemic preconditioning. These data suggest that these diseased hearts may require optimal preconditioning protocols or that they could be chronically preconditioned to resist ischaemic insult.