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Purpose Autoantibodies (aAbs) to type I interferons (IFNs) have been found in less than 1% of individuals under the age of 60 in the general population, with the prevalence increasing among those over 65. Neutralizing autoantibodies (naAbs) to type I IFNs have been found in at least 15% of patients with life-threatening COVID-19 pneumonia in several cohorts of primarily European descent. We aimed to evaluate the prevalence of aAbs and naAbs to IFN-α2 or IFN-ω in Japanese patients who suffered from COVID-19 as well as in the general population. Methods Patients who suffered from COVID-19 ( n = 622, aged 0–104) and an uninfected healthy control population ( n = 3,456, aged 20–91) were enrolled in this study. The severities of the COVID-19 patients were as follows: critical ( n = 170), severe ( n = 235), moderate ( n = 112), and mild ( n = 105). ELISA and ISRE reporter assays were used to detect aAbs and naAbs to IFN-α2 and IFN-ω using E. coli -produced IFNs. Results In an uninfected general Japanese population aged 20–91, aAbs to IFNs were detected in 0.087% of individuals. By contrast, naAbs to type I IFNs (IFN-α2 and/or IFN-ω, 100 pg/mL) were detected in 10.6% of patients with critical infections, 2.6% of patients with severe infections, and 1% of patients with mild infections. The presence of naAbs to IFNs was significantly associated with critical disease ( P = 0.0012), age over 50 ( P = 0.0002), and male sex ( P = 0.137). A significant but not strong correlation between aAbs and naAbs to IFN-α2 existed ( r =  − 0.307, p value < 0.0001) reinforced the importance of measuring naAbs in COVID-19 patients, including those of Japanese ancestry. Conclusion In this study, we revealed that patients with pre-existing naAbs have a much higher risk of life-threatening COVID-19 pneumonia in Japanese population. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-022-01308-3.

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