Sickle cell disease (SCD) is an autosomal recessive hemoglobinopathy characterized by increased cellular adhesiveness. Vaso-occlusion (VOC) is the most prevalent disease complication of SCD that could be altered by genetic factors. L-Selectin and integrin alpha 2 (ITGA2) are 2 adhesion molecules linked to vasculopathy and inflammation. The current study aimed at detecting the prevalence of genetic variants of L-selectin and ITGA2 as possible molecular modulators and novel therapeutic targets in a cohort of pediatric SCD patients. Genotyping was performed by polymerase chain reaction restriction fragment length polymorphism technique for 100 SCD patients and 100 age and gender-matched unrelated healthy controls. The homomutant genotype of ITGA2 C807T was significantly higher in SCD patients compared with controls (P=0.001) and confirmed almost a 3-fold increased risk of moderate and severe attacks of VOC. There are significant adverse effects caused by the polymorphisms of ITGA2, and hence Egyptian SCD patients could benefit from the targeted therapies specifically against ITGA2 to ameliorate the severe course of the disease and improve the quality of life. However, further studies of genotypes and expression levels of these adhesion molecules during the attacks of VOC are recommended.