The aim of the study was to investigate, whether (a) patients with homozygous sickle cell disease (SCD, HbSS) have abnormal blood fatty acids; (b) the abnormality, if it exists, affects all the plasma and erythrocyte lipids or it is restricted to a particular lipid moiety; (c) there is an association between levels of membrane n-3 or n-6 long-chain polyunsaturated fatty acids (LCPUFA) and the degree of anaemia. Fatty acids of erythrocyte choline (CPG), serine (SPG) and ethanolamine (EPG) phosphoglycerides and sphingomyelin (SPM); and plasma CPG, triglycerides and cholesterol esters of 43 steady-state HbSS patients and 43 ethnically matched, healthy, HbAA controls were analysed. The levels of the n-6 LCPUFA, arachidonic (AA), adrenic and docosapentaenoic acids in erythrocyte CPG (P<0.001) and EPG (P<0.01) were higher in the patients compared with the controls. In contrast, the proportions of eicosapentaenoic acid (EPA) in CPG and EPG (P<0.001) and docosahexaenoic acid (DHA) and total n-3 metabolites in CPG (P<0.001) were lower in the patients. The steady-state haemoglobin level of the patients correlated with erythrocyte DHA (r=0.55, P<0.01), EPA (r=0.38, P<0.05) and total n-3 metabolites (r=0.51, P<0.001) in CPG. Also, it correlated with erythrocyte EPA (r=0.64, P<0.01) and total n-3 metabolites (r=0.42, P<0.01) in EPG. The study revealed an imbalance between n-3 and n-6 LCPUFA in erythrocyte and plasma lipid moieties of the HbSS group. Furthermore, it suggested that correction of the imbalance by supplementation with EPA and DHA could ameliorate anaemia in the patients. This observation is consistent with the results of pilot studies, which demonstrated that treatment with n-3 fatty acids confers clinical benefit to sickle cell patients.