Obstructive sleep apnea (OSA) is associated with cardiovascular diseases such as hypertension through mechanisms involving intermittent hypoxia (IH). However, it is not yet clear whether IH directly affects the heart. In a mouse model of OSA, we found that IH causes time-dependent alterations of the susceptibility of the heart to oxidative stress. Acute IH can exert preconditioning-like cardioprotection, in part, through the transcriptional activation of genes such as bcl-x(L) and gata4. We cloned the mouse gata4 promoter and identified an IH-responsive region. The exposure of mice to prolonged IH results in the increased susceptibility of the heart to ischemia-reperfusion injury by increasing the oxidative stress status. This might resemble conditions of OSA patients. In our mouse model, further exposure to prolonged IH allowed reversal of the enhancement of myocardial damage. Understanding the complex effects of IH on the heart should help ultimately to develop therapeutic strategies against OSA-induced complications.