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Background: Sickle cell disease (SCD) disrupts oxygen transport due to the abnormal shape and rigidity of red blood cells, leading to hemolysis. Hemolysis, a major co-morbidity in SCD, is indicated by elevated levels of lactate dehydrogenase (LDH). Arginine depletion, which is essential for nitric oxide (NO) synthesis, contributes to various complications in SCD. L-arginine supplementation may increase NO levels and reduce oxidative stress. Research on its benefits in SCD, which is prevalent in sub-Saharan Africa, is limited. This study evaluates the effect of arginine supplementation on LDH levels in patients with steady state SCD., Methods: In a retrospective study, we evaluated the effect of arginine supplementation on LDH levels in a cohort of 31 patients. We divided the study into three phases: pre-HU treatment, HU treatment, and combined HU and arginine supplementation., Results: The cohort had a median age of 12 years, ranging from 2 to 43 years. Throughout all three phases of the study, lactate dehydrogenase (LDH) levels were consistently above the established normal ranges, with elevations of 216.7%, 220.3% and 176.6% above the normative values for baseline, Phase 1 (HU) and Phase 2 (HU + Arg), respectively. Specifically, LDH levels were 649.7 ± 364.2 U/L in Baseline Phase, 661.6 ± 367 U/L in Phase 1, and 529.9 ± 346.3 U/L in Phase 2. When comparing these discrete study intervals, it is noteworthy that LDH levels were significantly lower in Phase 2 compared to the previous phases ( p  = 0.002)., Conclusion: Preliminary findings revealed a significant lower LDH levels among sickle cell patients receiving combined arginine supplementation and hydroxyurea (HU). Although these findings are promising, their credibility and applicability require further and more extensive research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Ngonde, Lukanu, Mubiala and Aloni.)