Our previous cross-sectional study of patients with thalassemia major suggested progressive lung changes characterized by low total lung capacity, hypoxemia, and elevated transfer factor for carbon monoxide. We reevaluated nine of the patients for three reasons: to determine the relationship of the previous findings to the immediate effects of blood transfusion; to assess the longitudinal progression of the lung changes; and to evaluate the effect of splenectomy on lung volume changes in these patients, all of whom underwent splenectomy in the interval between the two studies. We found that during the 5- to 6-yr period between studies total lung capacity had decreased significantly (p less than 0.05) from a mean 86% predicted to a mean 79% predicted. However, vital capacity increased significantly (p less than 0.05) from a mean 81% predicted to 88% with no significant change in functional residual capacity. There was no significant immediate effect of transfusion on total lung capacity, vital capacity, or functional residual capacity. However, the diffusion constant for carbon monoxide increased significantly (p less than 0.005) immediately following transfusion and there was a positive correlation between the increase and the amount of blood transfused (r = 0.74, p less than 0.05). Arterial oxygen saturation was below 95% in five of eight patients and increased significantly with transfusion (p less than 0.05). We conclude: 1) thalassemia major and/or its treatment is associated with hypoxemia and a progressive reduction in total lung capacity. 2) Despite the progressive reduction in total lung capacity, splenectomy in patients with thalassemia major increases expiratory reserve volume and thereby increases vital capacity.