1. The number of adult patients undergoing surgery for congenital cyanotic defects in childhood has increased significantly. Therefore, the aim of the present study was to examine the effect of perinatal hypoxia on the tolerance of the adult myocardium to acute ischaemia-reperfusion injury. 2. Pregnant Wistar rats were exposed to intermittent hypobaric hypoxia 7 days before delivery; pups were born under normoxic conditions and exposed to hypoxia again for 10 postnatal days. After the last hypoxic exposure, all animals were kept for an additional 3 months under normoxic conditions. All experiments were performed on 90-day-old rats. 3. Ventricular arrhythmias were assessed on isolated perfused hearts during 30 min occlusion of the left anterior descending coronary artery. Infarct size was measured on isolated hearts (40 min regional ischaemia and 120 min reperfusion) and on open-chest animals (20 min regional ischaemia and 3 h reperfusion). 4. Perinatal exposure to hypoxia significantly increased cardiac tolerance to ischaemic injury in adult females, as evidenced by the lower incidence and severity of ischaemic ventricular arrhythmias, compared with the normoxic group. The effect of perinatal hypoxia on ischaemic arrhythmias in males was quite the opposite. Myocardial infarct size measured in open-chest animals only was significantly smaller in normoxic females compared with normoxic males. Perinatal exposure to hypoxia had no effect on infarct size in either setting or sex. 5. The results of the present study support the hypothesis that perinatal hypoxia is a primary programming stimulus in the heart that may lead to sex-dependent changes in cardiac tolerance to acute ischaemia in later adult life. This would have important implications for patients who have experienced prolonged hypoxaemia in early life.