Fatty acids are precursors of inflammatory oxylipins. In the context of COVID-19, an excessive production of pro-inflammatory cytokines is associated with disease severity. The objective was to investigate whether the baseline omega 3/omega 6 fatty acids ratio and the oxylipins were associated with inflammation and oxidative stress in unvaccinated patients with COVID-19, classified according to the severity of the disease during hospitalization. This Prospective population-based cohort study included 180 hospitalized patients with COVID-19. The patients were classified into five groups according to the severity of their disease. Group 1 was the least severe and Group 5 was the most severe. Three specific types of fatty acids-eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA)-as well as their enzymatic and non-enzymatic oxylipins were determined using chromatography coupled mass spectrometry. There was no difference in the ratio of omega-3 to omega-6 fatty acids between the groups (p = 0.276). However, the EPA/AA ratio was lower in Group 4 compared to Group 1 (p = 0.015). This finding was associated with an increase in both C-Reactive Protein (p < 0.001) and Interleukin-6 (p = 0.002). Furthermore, the concentration of F-Isoprostanes was higher in Group 4 than in Group 1 (p = 0.009), while no significant changes were observed for other oxylipins among groups. Multivariate analysis did not present any standard of biomarkers, suggesting the high complexity of factors involved in the disease severity. Our hypothesis was confirmed in terms of EPA/AA ratio. A higher EPA/AA ratio upon hospital admission was found to be associated with lower concentration of C-Reactive Protein and Interleukin-6, leading to a better prognosis of hospitalized SARS-CoV-2 patients. Importantly, this beneficial outcome was achieved without any form of supplementation. The trial also provides important information that can be further applied to reduce the severity of infections associated with an uncontrolled synthesis of pro-inflammatory cytokines.Trial registration: https://clinicaltrials.gov/study/NCT04449718 -01/06/2020. ClinicalTrials.gov Identifier: NCT04449718.