Background and Aims Previous studies have shown that supplementation of some amino acids such as l ‐arginine or its precursors could exert beneficial effects in patients with sickle cell disease (SCD). The objective of this study is to systematically review the literature to assess the effect of arginine administration on the clinical and paraclinical parameters of patients with SCD. Methods Four online databases of PubMed, Web of Sciences, Scopus, and Embase were selected for systematic search. Eligible studies were clinical trials that evaluated the effect of arginine usage in patients with SCD. Effects sizes were calculated using weighted mean difference (WMD) and Hedge's g and they were pooled using random‐effects modeling with Hartung–Knapp adjustment. Additional analyses were also conducted. Results Twelve studies containing detail of 399 patients with SCD were found to be eligible. The data synthesis showed that l ‐arginine significantly increased the level of NO metabolites (Hedge's g: 1.50, 0.48–1.82, I 2 : 88%) and hemoglobin F (WMD: 1.69%, 0.86–2.52, I 2 : 0%) and significantly decreased systolic blood pressure (WMD: −8.46 mmHg, −15.58 to −1.33, I 2 : 53%) and aspartate transaminase (Hedge's g: −0.49, −0.73 to −0.26, I 2 : 0%). However, there were no significant effects on hemoglobin, reticulocyte, malondialdehyde and diastolic blood pressure, and alanine transaminase. Conclusion Our meta‐analysis showed that l ‐arginine use for SCD could be beneficial, increase hemoglobin F and exert blood pressure‐lowering and hepatoprotective properties. However, for a firm conclusion and widespread use of l ‐arginine for these patients, more studies are needed.

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