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Objective: S-Adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) are indicators of global transmethylation and may play an important role as markers of severity of COVID-19., Methods: The levels of plasma SAM and SAH were determined in patients admitted with COVID-19 ( n = 56, mean age = 61). Lung injury was identified by computed tomography (CT) in accordance with the CT0-4 classification., Results: SAM was found to be a potential marker of lung damage risk in COVID-19 patients (SAM > 80 nM; CT3,4 vs. CT 0-2: relative ratio (RR) was 3.0; p = 0.0029). SAM/SAH > 6.0 was also found to be a marker of lung injury (CT2-4 vs. CT0,1: RR = 3.47, p = 0.0004). There was a negative association between SAM and glutathione level ( ρ = -0.343, p = 0.011). Interleukin-6 (IL-6) levels were associated with SAM ( ρ = 0.44, p = 0.01) and SAH ( ρ = 0.534, p = 0.001) levels., Conclusions: A high SAM level and high methylation index are associated with the risk of lung injury in patients with COVID-19. The association of SAM with IL-6 and glutathione indicates an important role of transmethylation in the development of cytokine imbalance and oxidative stress in patients with COVID-19., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2021 Evgeny Vladimirovich Kryukov et al.)