Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disorder characterized by thrombocytopenia with or without mucocutaneous bleeding manifestations. ITP patients have significant defects in immune self-tolerance: autoreactive T-lymphocyte clones are capable of directly damaging platelets and possibly megakaryocytes and are likely to proliferate under the influence of Th lymphocytes. The CB2 receptor is thought to be the principal cannabinoid receptor that mediates immune modulation by endocannabinoid. The later has shown a complex range of immunomodulatory effects, primarily suppressive effects on leukocytes and immune functions, including modulation of Th cell development, chemotaxis and cytokine secretion. In this study, we investigated the association between cannabinoid CB2 receptor gene (CNR2) Q63R polymorphism and the susceptibility to childhood ITP in Egyptian population. CNR2 genotyping in ITP patients revealed that 41% of patients had the QR(AA/GG) heterotype and 49% had the RR(AA/AA) homotype. There was a significantly higher frequency of homomutant genotype (RR) in ITP patients than in controls, which conferred more than two-fold increased risk of ITP among Egyptian children [odds ratio (OR) 2.352, 95% confidence interval (CI) 1.313–4.215]. There was a significant statistical difference in the distribution of CNR2 Q63R genotypes between chronic ITP patients group and the control groups. The homomutant genotype carried nearly three-fold increased risk for chronic ITP (OR 2.701, 95% CI 1.462–5.009). In conclusion, CNR2 Q63R polymorphism may represent a novel genetic risk factor in the pathophysiology of chronicity development of ITP in Egyptian children.