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Introduction: Hyperoxia is an easy access preconditioner which attracts the researcher to use it in the clinic. Drug dependence is a widespread prevalence among different societies and one of the confounding factors in many diseases. Among different drugs, morphine dependence has shown preconditioning effects. According to both widespread phenomenon of drug addiction and use of hyperoxia in the clinic, there is a high probability of interaction between these two preconditioner factors on the ischemia-reperfusion injuries. Therefore, in this study, interaction of these two preconditioners on the ischemia-reperfusion injuries has been investigated. Method: Each containing ten rats, hearts were isolated in langendorff setup and after local ischemia, release of creatine phosphokinase (as a tissue damage index) and rate pressure product (as a mechanical function index) were measured. Furthermore, episode numbers of ventricular tachycardia and ventricular fibrillation (as arrhythmias indices) during ischemia and reperfusion period were studied separately. Results: normobaric hyperoxia in isolated morphine dependent rat hearts decreased creatine phosphokinase and increased mechanical function during reperfusion period. However, there was no significant difference in arrhythmias toward each of these preconditioners alone. Conclusion: preconditioning with normobaric hyperoxia in isolated morphine dependent rat heart induced reduction of tissue damage and improved cardiac function.