Despite the introduction of deferoxamine, 50% of thalassaemia major patients die before the age of 35 years predominantly from iron induced heart failure. Indeed, the assessment of myocardial performance may be of particular interest since it can reveal an early myocardial dysfunction. By using impedance cardiography and mass spectrometry, we studied the cardiac function and the oxygen extraction ratio (O(2)ER) of 14 thalassaemic patients and 15 control healthy subjects during an incremental cycle-ergometer test. The achieved mechanical power output and the relative O(2) uptake did not reach any significant difference between groups. At the highest workload, O(2)ER reached significantly higher values in thalassaemic patients versus control subjects while the relationship between cardiac index (CI) and O(2)ER (CI/O(2)ER) decreased showing a lower contribution of cardiovascular system to maintain O(2) uptake. Results of this study imply that CI/O(2)ER allows an early diagnosis of the iron induced myocardial dysfunction, whereas it is not clinically patent yet. To our knowledge, this is the first study revealing an O(2)ER pivotal role as compensatory mechanism to maintain a normal working capacity in subjects suffering from thalassaemia major.