To determine the predominant abnormality of pulmonary function in patients with thalassemia major (TM), we evaluated 29 patients with TM who were receiving hypertransfusion therapy and chelation with desferrioxamine (DFO), and who ranged in age from 6 to 40 yr (mean 19.8 +/- 8.5 yr). A reduction in the total lung capacity (TLC) was the most striking abnormality, found in 21 of 29 patients (79%). Fourteen of these patients (67%) had a moderate or severe reduction in TLC. Expiratory flow rates, FEV1, and FEF25-75 were decreased below predicted values in 48 and 17% of the patients, respectively, but no patients had pure obstructive disease. Significant hypoxemia (oxygen saturation of less than 95%) was observed in only one patient. There was a significant inverse correlation between TLC and patient age (p < 0.003), transfusional iron burden (p < 0.003) and DFO ratio (p < 0.024). Restrictive disease is the predominant abnormality of pulmonary function in TM, with a mixed restrictive-obstructive pattern in a small number of patients. The restrictive disease becomes more severe with increasing age, and the degree and duration of iron overload appear to be important in its pathogenesis. The role of DFO therapy in preventing the pulmonary complications associated with TM requires further study.