COVID-19 patients with a mild course had significantly higher HMGB1 levels compared to healthy individuals before treatment (18.7 (IQR 12.5–22.1) vs. 7.3 (IQR 6.6–9.0) μg/L, p = 0.021), but showed no significant difference from either ARDS cohort (ARDS with COVID-19 19.6 μg/L (IQR 10.0–30.2), p = 0.92 and ARDS without COVID-19 33.6 μg/L (IQR 23.3–62.4), p = 0.29). Here, HMGB1 is linked to acute respiratory distress syndrome.