Ca2+ overload induced by ischemia-reperfusion alters Ca2+ homeostasis, which plays an important role in myocardial cell injury. Although desflurane has been commonly used in anesthesia, little is known about its cardioprotective effect associated with Ca2+ homeostasis in ischemia-reperfused rat heart. Artificially ventilated anaesthetized Sprague-Dawley rats were subjected to a 30 min of left anterior descending coronary artery occlusion followed by 2 h of reperfusion. Rats were randomly assigned to one of three groups; Sham, I/R only, desflurane preconditioning group. In the present study, desflurane reduced infarct size (43.6±5.5% vs. 19.1±1.9% for I/R and desflurane, respectively, p<0.01). In desflurane-treated rat heart, we observed a consistent decrease in the expression of pro-apoptotic protein Bax leading to a decrease in cytochrome c release. We also found that desflurane enhanced expression of anti-apoptotic protein Bcl-2, activated ERK concerned with survival, and significantly attenuated abnormal changes of sarcoplasmic reticulum genes and proteins in ischemia-reperfused rat heart. These results suggest that desflurane prevents myocardial injury in response to ischemia-reperfusion by modulating sarcoplasmic reticulum function.