The severity of sickle cell disease (SCD) in terms of frequency of vaso-occlusive crises may be affected by variation in genes coding for enzymes involved in fatty acid metabolism. The understanding of genomic factors that affect disease severity may be enhanced by investigating the relationships between the frequency of sickle-related vaso-occlusive crises and Single Nucleotide Polymorphisms (SNPs) variation in Fatty Acid Desaturase II (FADS2) gene. The aim is to determine the effect of the variation in FADS2 gene on the frequency of painful crises and other clinical correlates in sickle cell anaemia patients in Enugu, Nigeria. This was a cross-sectional study of 100 consecutive sickle cell anaemia patients receiving care at the University of Nigeria Teaching Hospital, Enugu, Nigeria between May 2013 and February 2014.The eligible patients were categorized into two groups namely; group A and group B. Group A (those with moderate to severe crisis), formed the study group comprising those who have had two or more sickle cell painful crises in the last one year preceding the study but currently in steady state, while group B (control group with mild crisis), comprised sickle cell anaemia patients matched for age, sex, highest educational status, and occupation but who have had no painful crisis or had only one painful crisis (0 – 1 crises) in the last one year preceding the study and currently in steady state. Also, the clinical severity will be measured by both laboratory parameters: white cell count, 2 haemoglobin concentration, platelet count and neutrophil percentage and by presence of end organ damage, number of blood transfusions, number of hospital visitations/admissions The overall mean age of the patients was 18.4 ± 12.2 (range: 2-52) years. A total of 20 variant Single Nucleotide Polymorphisms (SNPs) including rs968567, rs116646028, rs71956563, and rs12281373 were detected following DNA extraction, gene sequencing and analysis for the FADS2 gene in both groups of patients. Of these 20 SNPs; 19 were found among patients in Group A while 1 was found among patients in Group B. The observed difference was statistically significant [23/50(24%) vs. 1/50(2%); OR: 13.8; P = 0.01]. The mean values of the haematological parameters including haemoglobin concentration, white cell count, platelet count, and neutrophil count were significantly higher in patients with SNPs than those without SNPs (P < 0.05). Similarly, the proportions of patients with most of the sickle cell related complications were significantly higher among patients with SNPs than those without SNPs (P < 0.05). In conclusion therefore, structural variations in the genes coding for FADS2 could be contributory to the degree of clinical severity of sickle cell anaemia including the frequency of crises. Since most complications of sickle cell anaemia including frequency of crises are associated with raised levels of haematological parameters, future preventive interventions may be targeted at controlling the blood levels of these cells.