Objective: To determine the frequency of beta s globin gene haplotypes in Nigerian patients with sickle cell disease (SCD) and to measure their correlation with clinical and haematological characteristics. Methods: This study enrolled patients with SCD and collected their peripheral blood for restriction fragment length polymorphism analysis in order to identify five polymorphic sites in the β-globin gene cluster. Results: A total of 245 homozygous SCD patients (490 alleles) were included in the study. Among the analysed alleles, 426 (86.9%) had the Benin (BEN) haplotype; 19 (3.9%) had the Senegal (SEN) haplotype; 31 (6.3%) had the Cameroon haplotype; five (1.0%) had the Bantu/Central African Republic haplotype; and nine 9 (1.8%) had atypical haplotypes. No significant association was observed between the haplotypes and haematological events, although patients with the BEN/SEN haplotype showed improved red blood cell counts, haemoglobin levels and red blood cell width index. No significant association was observed between the haplotypes and the three clinical manifestations, although patients with the BEN/SEN haplotype showed a four-fold lower frequency of painful episodes. Conclusion: These findings suggest that the SEN haplotype combined with the BEN haplotype might contribute toward a better haematological profile and milder clinical severity in SCD.