Pulmonary function tests were performed on 62 transfusion-dependent patients with thalassemia major ranging in age from 8 to 33 years, on chelation therapy with desferoxamine or deferiprone. Percentage predicted forced vital capacity (FVC), expiratory volume in one second (FEV1), and peak expiratory flow (PEF) were significantly reduced, while FEV1/FVC and maximal expiratory flow at 25% FVC were within normal limits, indicating a restrictive disease. Both FVC and FEV1 were negatively correlated with transfusional iron burden as indexed by age. Single-breath carbon monoxide transfer factor was reduced, even after correction for low hemoglobin concentration, and was negatively correlated with iron burden and iron overload, as indexed by serum ferritin levels. Owing to low hemoglobin concentration, blood diffusing capacity was reduced, in spite of increased lung capillary blood volume, which was, however, adequate to normalize blood diffusing capacity when hemoglobin concentration was only partially restored by transfusion. The diffusing capacity of the alveolar-capillary membrane was substantially decreased and negatively correlated with age and serum ferritin, the fall being primarily attributed to an increased membrane thickness. These findings suggest that lung fibrosis and/or interstitial edema related to iron overload are the main cause of pulmonary dysfunctions observed in patients with thalassemia major.