The purpose of our study was assessment of the relative contribution of the systems involved in blood gas exchange to the limited exercise capacity in patients with beta-thalassemia major (TM) using integrative cardiopulmonary exercise testing (CPET) with estimation of oxygen kinetics. The study consisted of 15 consecutive TM patients and 15 matched controls who performed spirometric evaluation, measurement of maximum inspiratory pressure (Pimax) and an incremental symptom-limited CPET on a cycle ergometer. Exercise capacity was markedly reduced in TM patients as assessed by peak oxygen uptake (pVO(2), mL/kg/min: 22.1+/-6.6 vs 33.8+/-8.3; P<0.001) and anaerobic threshold (mL/kg/min: 13.0+/-3.0 vs 18.7+/-4.6; P<0.001) compared with controls. No ventilatory limitation to exercise was noted in TM patients (VE/VCO(2) slope: 23.4+/-3.2 vs 27.8+/-2.6; P<0.001 and breathing reserve, %: 42.9+/-17.0 vs 29.5+/-12.0; P<0.005) and no difference in oxygen cost of work (peak VO(2)/WR, mL/min W: 12.2+/-1.7 vs 12.2+/-1.5; P=NS). Delayed recovery oxygen kinetics after exercise was observed in TM patients (VO(2)/t slope, mL/kg/min(2): 0.67+/-0.27 vs 0.93+/-0.23; P<0.05) that was significantly correlated with Pimax at rest (r: 0.81; P<0.001). The latter was also significantly correlated to pVO(2) (r: 0.84; P<0.001) and inversely correlated to ferritin levels (r: -0.6; P<0.02). Exercise capacity is markedly reduced in TM patients and this reduction is highly associated with the limited functional status of peripheral muscles.