In sickle cell anaemia (SCA), continuous activation of the vascular endothelium by inflammatory cytokines leads to increased elaboration and secretion of von Willebrand Factor (vWF), a potent mediator of adhesive interactions involving the endothelium and circulating blood cells. Non-O blood groups are associated with the elevation of vWF concentration. Thus, SCA and non – O blood groups are determinants of increased levels of vWF, which plays a pivotal role in the pathophysiology of vaso-occlusive crisis (VOC). To determine the influence of plasma vWF:Ag levels, ABO and Rh (D) blood groups on the risk of occurrence of sickle cell vaso-occlusive crisis. We conducted a prospective study of frequencies of VOC with respect to plasma vWF:Ag levels, ABO and Rh (D) blood groups of 50 SCA patients. In comparison with blood group O, patients with non – O blood groups had significantly higher mean vWF concentration (4.17+3.16 IU/l vs 3.46+3.69 IU/l, p< 0.001), with a significantly higher mean number of VOC episodes per patient (3.2 vs 1.3, p<0.001). The relative risk of VOC for patients with non- O blood groups was 1.87 (95% confidence interval 1.5 - 2.2, p<0.001). However, the association of Rh (D) blood group of the patients and their plasma vWF:Ag levels on the risk of occurrence and frequency of VOC was not statistically significant (P = 0.155). SCA patients with non – O blood groups had more episodes and higher risk of VOC that were likely due to the effect of higher plasma vWF concentration. These results indicate that the non- O blood group is a risk factor for frequent VOC and an unfavourable prognostic marker in SCA. We hereby recommend that a large multicentre prospective study be carried out to definitely determine the impact of ABO, Rh and other blood groups on the overall clinical course of SCA.