Sickle cell disease (SCD) is a chronic inflammatory disease associated with increased levels of multiple cytokines as interferon gamma (IFN-γ) during vaso-occlusive (VOC) crisis and steady state. Therefore, we aimed to explore theimmunological role of serum IFN-γ, interleukin-10 (IL-10) and CD4⁺ T lymphocytes in children with SCD at steady state and VOC. This study was conducted on 30 children with SCD (15 at steady state and 15 in VOC) and 30 healthy children as controls. Detailed history, complete physical, clinical examination and laboratory investigations as: complete blood count, serum ferritin, IFN-γ, IL-10 and CD4⁺ T lymphocytes for all patients were recorded. Results: Significant increase in serum IFN-γ in patients with SCD during VOC compared with patients at steady state and controls (P<0.001). Significant increase in serum IL-10 in patients with SCD at steady state compared with those during VOC and controls (P=0.008 and P=0.04 respectively). CD4 ⁺T lymphocyte decreased in patients with SCD during VOC compared with those at steady state and controls (P<0.001). There was a significant positive correlation between serum IFN-ɣ and number of crisis per year (r=0.648, P=0.0001). Serum IFN-γ was increased in patients with history of frequent crisis per year (P=0.001) and decreased in patients under hydroxyurea therapy (P<0.001). IFN-γ was increased in SCD patients. Increased IFN-γ production in SCD suggesting that functionally activated natural killer cells reflecting a host immunological mechanism leading to antigen antibody activation in SCD. Serum IL-10 increased in SCD patients at steady state. CD4 ⁺T lymphocyte decreased in patients during VOC.