Background: Lung impairment represents one of the complications of thalassemia major whose clinical picture can remain in subclinical form all life long. Few works have been published and the results are contradictory. Objectives: The aim of this study was to determine the spirometric pattern, the age of onset in thalassemic boys and girls, and to investigate the association with the onset of endocrinological complications. Methods: We studied 48 patients, divided into three groups according to pubertal stages, in order to better distinguish the periods of life in which different endocrinological complications usually appear. Group A: (n = 14; 8 F, 6 M; age 10.8 ± 1.7 years): prepubertal patients; group B (n = 21; 10 F, 11 M; age 15.7 ± 1.1 years): pubertal patients; and group C (n = 13; 9 F, 4 M; age 19.0 ± 1.4 years): postpubertal patients. Pulmonary function tests (PFTs) and diffusing capacity for carbon monoxide (DCO), corrected for both Hb values (DCO*) and alveolar volume (KCO), were performed 2 days after blood transfusion and were considered pathologic when they fell below 80% of the predicted value. Results: All patients in group A showed normal PFTs, DCO* and KCO values, as well as normal endocrinological assessment. By contrast, all those in group C showed a restrictive spirometric pattern with reduced DCO* (63 ± 8%), elevated KCO values (120 ± 14%), a variable degree of hypoxia (PO2 82 ± 9%), and high serum ferritin levels. Only 2 patients showed a radiological picture of interstitial fibrosis. Furthermore, 9 patients had hypogonadism and 3 hypothyroidism. In group B, only 3 patients showed a restrictive pattern and 1 of them reduced DCO* values, and 2 out of 3 patients had hypogonadism. Considering all patients on the whole, DCO* was negatively correlated with both serum ferritin (r = –0.58; p < 0.05) and age (r = –0.57; p < 0.05). Conclusions: The presence of a restrictive pattern in 16 older patients associated with both high serum ferritin levels and endocrinological complications in a lot of them was the main feature in this study. Iron overload might be the main factor determining lung impairment, even though a more accurate evaluation is necessary. Possible pathological mechanisms and the role of the genotype are discussed.