Background: Folic acid is a hydro-soluble vitamin that classifies as part of the vitamin B complex. The coenzymes of folic acid are actively involved in the one-carbon metabolism. It was established that folate metabolism is involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).The study aimed to investigate that decreased folate levels with hypoxia may involve in patients with COVID-19 Methods: The study was performed between September 2021 to January 2022. A 75 subjects were enrolled in this study with COVID-19 (moderate =35, severe=45) with mean age (56 ± 1.6; 37 males, 38 female), and 45 subjects appeared to be normal healthy persons as the control group with mean age (41 ± 1.5; 17 males, 28 female) Folic acid levels was measured by colorimetric method. Serum 5-MTHF, HIF-1α, and TNF-α were measured by ELISA. Results: : The results clearly showed low folic acid and its derivative 5-MTHF levels in patient groups with COVID-19 compared to control (P<0.01); a great effect was shown in the severe group. The finding also declared that serum level of TNF-α and HIF-1α were significantly increased in patients with COVID-19 infection compared to control groups (p <0.01). Conclusions: The main findings may go some way towards establishing a link between folic acid status, a hypoxia and COVID-19 prevalence, with a possible association to the disease severity. Therefore, folic acid supplementation may protect against COVID-19
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