Low L- arginine concentration ([R]) has been reported in sickle cell anaemia (SCA). L- Arginine supplementation may be a cheaper alternative to the very expensive inhalation of nitric oxide in the management of SCA in Nigeria. The study investigated the effect of low-dose (1 g/day), oral L- arginine (Mason Vitamins, INC. USA) supplementation on plasma [R], lipid peroxidation (LPx), total antioxidant activity (TAA), red cell osmotic fragility and irreversibly sickled cell (ISC) count. 33 male and female non-sickle cell anemia subjects (NSCAS) and 28 sickle cell anaemia subjects (SCAS) were studied. A written ethical approval was granted for the study (Medical Research Grant and Experimentation Ethics Committee, College of Medicine University of Lagos, Nigeria). Each subject gave informed consent. 5 mL of venous blood was withdrawn from an ante-cubital vein of each subject for the measurements of plasma [R] (Li et al., 2008), malondialdehyde ([MDA] for LPx), TAA (Koracevic et al., 2001), osmotic fragility and ISC count. L- Arginine was then taken orally (1 g/day/6 weeks, Tanimura, 1967) by each subject. Measurements were made before and after L- arginine supplementation. Before supplementation, TAA (1.0±0.1 vs 1.5±0.2 mM/L, P<0.05) and [R] (8.3±0.7 vs 12.4±0.5 mg/dL, P<0.001) were low in SCAS compared to NSCAS while [MDA] (41.4±0.4 vs 33.0±2.0 mM/mg prot, P<0.001), initial lysis (IL: 0.86±0.01 vs 0.63±0.02 g%, P<0.001) and mean corpuscular fragility (MCF: 0.40±0.01 vs 0.45±0.01 g%, P<0.05) were high in SCAS compared to NSCAS. L- Arginine increased TAA (1.0±0.1 vs 1.6±0.2 mM/L in SCAS and 1.5±0.2 vs 2.0±0.1 mM/L in NSCAS, P<0.05) and [R] (8.3±0.7 vs 15.2±0.4 mg/dL in SCAS and 12.4±0.5 vs 18.8±0.6 mg/dL in NSCAS, P<0.001). However, [MDA] (41.4±0.4 vs 14.9±1.1 mM/mg prot in SCAS and 33.0±2.0 vs 14.2±0.7 mM/mg prot in NSCAS, P<0.001), IL (0.86±0.01 vs 0.57±0.02 g% in SCAS and 0.63±0.02 vs 0.49±0.02 g% in NSCAS, P<0.001), MCF (0.40±0.02 vs 0.23±0.01 g% in SCAS and 0.45±0.01 vs 0.22±0.02 g% in NSCAS, P<0.001), complete lysis (0.21±0.02 vs 0.11±0.02 g% in SCAS and 0.22±0.02 vs 0.01±0.01 g% in NSCAS, P<0.001), (and ISC count: 7.9±1.2 vs 2.0±0.3 %, P<0.001 in SCAS only) were reduced after supplementation. L- Arginine caused a greater percent increase in TAA (60.0±10 vs 33.0±6.7 %, P<0.05) and [R] (83.1±3.6 vs 51.6±0.8 %, P<0.001) while reduction in IL was greater (0.29±0.01 vs 0.14±0.01 g%, P<0.001) in SCAS than in NSCAS. Δ[R] correlated with ΔTAA (r=+0.8), Δ[MDA] (r=-0.7) and ΔISC (r=-0.6) in SCAS. Δ[R] correlated with ΔTAA (r=+0.6) and Δ[MDA] (r=-0.5) in NSCAS. Low-dose, oral L- Arginine improved TAA, red cell resistance to osmotic haemolysis and [R] but suppressed LPx in both groups of subjects and reduced ISC count in SCAS. L- Arginine may have beneficial implications in cost effective therapy in the management of SCA.