Background: Thalassemia is the most common monogenic disorder worldwide. In the most extreme conditions, thalassemia patients suffer from severe anemia necessitating regular blood transfusions (thalassemia major-TM). TM is particularly common in Southeast Asia, Middle East, and Mediterranean countries. TM represents a major health problem globally, with estimated general frequency of 3% - 4% rising up to 8% - 10% in some penetrant regions. Both quantitative and qualitative properties of immune cells, as well as cytokine profile of innate immunity are subjects for derangements in TM. Patients with TM are often encountered with a low-grade systemic inflammatory status with higher total leukocyte, neutrophil, and lymphocyte counts. Neutrophils isolated from TM patients’ demonstrated significantly lower functional activity in comparison with the cells derived from healthy controls. Higher expression of surface molecules such as CD11b, CD18, and CD69 on monocytes, and higher expression of CD11b, CD18, CD35, CD44, and CD67 on neutrophils have been described in TM. Mechanisms underlying attenuated neutrophilic function in TM are not well characterized. In one hand, chronic elevation of oxidative stress may interfere with function of these phagocytic cells. Besides, neutrophils of TM patients have been described with high expression of apoptotic markers; caspases 3,7,8, and 9. 3.2. Regarding the role of B lymphocytes in production of alloantibodies and autoantibodies against transfused red blood cells, humoral immunity function is a critical issue in TM. TM patients harbor larger B cell proportion compared to normal counterparts. B lymphocytes with a regulatory phenotype, expressing CD19, CD38, and CD24 have been identified with a significant higher ratio in TM patients than control subjects. Effects of splenectomy on pathogenesis of TM are controversial. Splenectomy has been noted to boost the number of both CD4+ and CD8+ T cells in TM patients. Splenectomy has also been associated with higher neutrophil counts. In contrast, splenectomy has been reported to reduce NKCs and CD4+ lymphocytes counts in the patients. Cytokines produced by activated immune cells including IL-2 and TNF-α were described to be higher in splenectomized TM patients.