Background <p>Albumin is the most abundant protein in the human circulation and has many important functions. Recent studies have shown that albumin is a free radical scavenger and can be oxidized to single (HNA-1) or double (HNA-2) oxidized albumin. Oxidized albumin is a predictor for mortality in liver disease, but little is known about oxidized albumin in other diseases. This study aims to explore oxidized albumin levels in critically ill Covid-19 patients and its association with hospital mortality.</p> Methods <p>In this single-center, retrospective cohort study we included Covid-19 patients (<i>n</i> = 164) treated on the ICU of Karolinska University Hospital between April 2020 and May 2021. Patient data were gathered from the electronic patient records. Oxidized albumin fractions were measured in plasma samples collected within the first 48&#xa0;h of ICU admission and compared with healthy volunteers (<i>n</i> = 10). To assess the clinical relevance of oxidized albumin, descriptive statistics were performed after dividing the study group in three tertiles based on HNA-1 levels and two groups based on the presence and absence of HNA-2. A post hoc multivariable linear regression analysis was performed to assess the correlation between oxidized albumin fraction and creatinine levels.</p> Results <p>HNA-1 levels were 5.1 percent point higher (<i>p</i> = 0.01) in Covid-19 patients than in healthy controls. There was no significant difference in HNA-2 levels. Hospital mortality, length of ICU stay and duration of mechanical ventilation did not differ significantly between patients with high levels of oxidized albumin and patients with low levels of oxidized albumin. Creatinine levels and sequential organ failure assessment (SOFA) scores were higher in patients with more oxidized albumin. Multivariable linear regression showed a weak but clinically relevant correlation between the fraction of oxidized albumin and creatinine, when corrected for age and chronic kidney disease before ICU admission (<i>R</i>² 0.31, <i>p</i> &lt; 0.001).</p> Conclusion <p>Fractions of HNA-1 were higher in Covid-19 patients compared to healthy controls. In critically ill Covid-19 patients elevated levels of oxidized albumin were not associated with higher hospital mortality. Higher HNA-1 levels were associated with higher creatinine levels and higher SOFA scores. These findings contribute to increased knowledge about oxidized albumin in critically ill Covid-19 patients and can inspire future research.</p>