Background: Vaso-occlusive crisis (VOC) is a significant cause of morbidity and mortality in sickle cell disease (SCD) patients. As polymorphisms in human platelet antigens (HPA) exhibit a prothrombotic nature, we hypothesized that specific HPA polymorphisms could have a role in the pathogenesis of VOC in SCD. Aim of Study: This study investigated HPA-3 T2622G among Egyptian SCD patients. Patients and Methods: This study included 100 SCD patients and 50 controls. Patients were divided into, VOC group (n=60), and steady-state group (n=40). Genotyping was done using PCR-based Restriction Fragment Length Polymorphism (RFLP) technique. Results: The HPA-3 mutant genotypes were significantly associated with SCD compared to controls (p=0.001), while no significant difference was observed between VOC and steady-state groups (p=0.169). Regarding the frequency of VOC episodes, the HPA-3 homozygous mutant genotypes showed significant differences (p=0.001). The HPA-3 mutant genotypes were significantly correlated with generalized type of VOC (p=0.006) and need for hospitalization (p=0.003). Regarding VOC complications, the HPA-3b/3b genotype was significantly associated with acute chest syndrome (p=0.008) and stroke (p=0.012). Conclusion: The HPA-3 T2622G is common among SCD patients. Although it is not a major determinant of vasculocclusion in SCD, it is significantly associated with VOC complications and may alter their outcome.