AbstractObjectives:  Vaso‐occlusive crisis (VOC) is a significant cause of morbidity and mortality in sickle cell anemia (SCA) patients. Insofar as polymorphism in human platelet alloantigen (HPA) exhibit a prothrombotic nature, we hypothesized that specific HPA polymorphic variants are associated with VOC. We investigated the distribution of HPA1, HPA2, HPA3, HPA4, and HPA5 alleles genotypes among VOC and non‐VOC control SCA patients.Patients/methods:  This was a case–control study. Study subjects comprised SCA patients with (VOC group; n = 127) or without (Steady‐state group; n = 130) VOC events. HPA genotyping was done by PCR‐SSP.Results:  Significantly higher frequencies of HPA‐2b, HPA‐3b, and HPA‐5b alleles, and marked enrichment of HPA‐3b/3b, HPA‐5a/5b, and HPA‐5b/5b genotypes, were seen in VOC than in control SCA patients. Taking homozygous wild‐type genotypes as reference, univariate analysis identified HPA‐3a/3b, HPA‐3b/3b, and HPA‐5b/5b to be associated with VOC. Multivariate analysis confirmed the independent association of only HPA‐3a/3b and HPA‐3b/3b genotypes with VOC. HPA‐3 genotypes were significantly correlated with VOC frequency, type, and medication, and requirement for hospitalization. While both HPA 3a/3b (P = 0.002; OR = 2.94; 95% CI = 1.49–5.77) and 3b/3b (P = 0.006; OR = 3.16; 95% CI = 1.40–7.17) genotypes were associated with need for hospitalization, only HPA‐3b/3b was associated with VOC frequency, type (localized vs. generalized), and medication (narcotics vs. NSAIDs).Conclusion:  This confirms the association of HPA polymorphisms with SCA VOC, of which HPA‐3 appears to be independent genetic risk factors for SCA VOC.