Here, we showed that neutralizing autoantibodies against IFNα (anti-IFN-I-Abs) cross-react with all IFNα subtypes in a cross-sectional and longitudinal cohort of patients with SLE and are associated with significantly reduced levels of circulating IFNα levels, disease activity, and restored B cell responses, suggesting a disease-aggravating role for non-neutralizing anti-IFN-Abs. Here, IFNA2 is linked to systemic lupus erythematosus.