Abstract Background: During the COVID-19 pandemic, the severity of symptoms have been coined to the over production of inflammatory cytokines with consequent immune hyperacti-vation. The cytokine storm is considered as a crucial cause of lung damage, multiorgan failure and mortality in COVID-19. Aim of Study: To evaluate the serum levels of TNF-a  and IL-10 in COVID-19 patients and to explore their potential relation with disease severity. Patients and Methods: The study was conducted during the period from November 2020 to March 2021 on 46 patients confirmed with COVID-19 and admitted to the isolation hospitals or recruited from the COVID-19 clinic of Kasr Al-Ainy Cairo University Hospitals and 45 matched healthy controls. Patients have undergone full history taking, clinical and radiologic examination and laboratory testing. All candi-dates were subjected to assessment of the serum levels of TNF-a  and IL-10 by enzyme-linked immunosorbent assay technique. Results: The serum levels of TNF-a  and IL-10 were significantly increased in COVID-19 patients compared to healthy controls, and their levels were higher with more disease severity. Significant correlations were observed be-tween serum TNF-a  with serum ferritin, CRP and IL-6 and between IL-10 with CRP and D-dimer. Both were inversely related to the lymphocytic counts in COVID-19 patients. Conclusion: The high levels of serum TNF-a  and IL-10 in COVID-19 highlights the pivotal role played by these cytokines in the immune pathogenesis of COVID-19. Their association with severe illness suggests they can possibly serve as reliable biomarkers for monitoring disease activity and predicting severity and outcome in COVID-19. Better understanding of the cytokine response pattern in COVID-19 would contribute to the improved development of more effec-tive immunomodulatory therapies for COVID-19 in the future.