The importance of spleen, spleen iron and splenectomy has been investigated in 28 male and 19 female β-thalassemia major (β-ΤΜ), adult patients. In one study, an increase from about five (615 g; 19.5 × 11.0 × 6.0 cm) to twenty (2030 g; 25.0 × 17.5 × 12.0 cm) times higher than the normal size and weight of spleen has been observed in twenty patients following splenectomy. In a second study, the mean size for the liver (19.4 cm, range 13.5-26.0 cm) and spleen (15.6 cm, range 7.0-21.0 cm) measured by magnetic resonance imaging (MRI) and by ultrasound imaging for spleen (15.1 cm, range 9.0-21.0 cm) of 16 patients indicated that on average the spleen is about 80% of the size of the liver. In the third study, comparison of the iron load using MRI T(2)* and iron grading of stained biopsies indicated that substantial but variable amounts of excess iron are stored in the spleen (0-40%) in addition to that in the liver. Following splenectomy, total body iron storage capacity is reduced, whereas serum ferritin (p = 0.0085) and iron concentration in other organs appears to increase despite the reduction in the rate of transfusions (p = 0.0001) and maintenance of hemoglobin levels (p = 0.1748). Spleen iron seems to be cleared faster than liver iron using effective chelation protocols. Spleen iron is a major constituent of the total body iron load in β-ΤΜ patients and should be regularly monitored and targeted for chelation. Normalization of the body iron stores at an early age could maintain the spleen in near normal capacity and secondary effects such as cardiac and other complications could be avoided.