Abstract We investigated whether or not Omega-3 long-chain polyunsaturated fatty acid (omega-3 LCPUFA) supplementation exacerbates oxidative stress in homozygous sickle cell patients aged 2 to 14 years. Depending on their age, they received between one and three omega-3 (277.8 mg DHA and 39.0 mg EPA/capsule) or placebo (high oleic acid sunflower seed oil) capsules for one year. Supplementation increased significantly the levels of the two fatty acids in red cell phosphatidylcholine and phosphatidylethanolamine ( p <0.001). The patients who received omega-3 LCPUFA compared with their placebo-taking counterparts had a higher concentration of plasma vitamin E at one year (14.3±2.8 versus 12.3±2.8 µmol/l; p <0.001). The two groups had comparable concentrations of the vitamin at six month intervention (10.8±2.2 versus 10.7±2.9 µmol/l; p >0.05) and baseline (10.7±3.1 versus 10.7±2.8 µmol/l; p >0.05). After six month of intervention, the patients on omega 3 fatty acids had lower GPx-1 (33.5±13.4 versus 46.6 ±17.6, p <0.01) and Cu/Zn-SOD (1070±600 versus 1470±690 p <0.05) activities than at baseline. GPx-1 (33.5±17.6 IU/g Hb versus 43.7±13.2 IU/g Hb; p <0.01) and Cu/Zn-SOD (1070±600 IU/g Hb versus 1360±920 IU/g Hb; p >0.05) activities were reduced in the omega 3 compared with the placebo at six month intervention. There was no difference in the activity of either of the enzymes between baseline and six month intervention in the placebo group ( p >0.05). This study demonstrates; DHA and EPA supplementation, rather than exacerbating the inherent oxidative stress associated with the disease, seems to provide an antioxidant protection. Hence, it will be safe to provide omega-3 LCPUFA to sickle cell patients to help ameliorate vaso-occlusive and haemolytic crises and membrane fatty acid abnormality.