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Preexisting anti–interferon-α (anti–IFN-α) autoantibodies in blood are associated with susceptibility to life-threatening COVID-19. However, it is unclear whether anti–IFN-α autoantibodies in the airways, the initial site of infection, can also determine disease outcomes. In this study, we developed a multiparameter technology, FlowBEAT, to quantify and profile the isotypes of anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and anti–IFN-α antibodies in longitudinal samples collected over 20 months from the airways and blood of 129 donors spanning mild to severe COVID-19. We found that nasal IgA1 anti–IFN-α autoantibodies were induced after infection onset in more than 70% of mild and moderate COVID-19 cases and were associated with robust anti–SARS-CoV-2 immunity, fewer symptoms, and efficient recovery. Nasal anti–IFN-α autoantibodies followed the peak of host IFN-α production and waned with disease recovery, revealing a regulated balance between IFN-α and anti–IFN-α response. In contrast, systemic IgG1 anti–IFN-α autoantibodies appeared later and were detected only in a subset of patients with elevated systemic inflammation and worsening symptoms. These data reveal a protective role for nasal anti–IFN-α in the immunopathology of COVID-19 and suggest that anti–IFN-α autoantibodies may serve a homeostatic function to regulate host IFN-α after viral infection in the respiratory mucosa. Editor's summary: Autoantibodies targeting interferon-α (IFN-α) have been found in the circulation of those with severe COVID-19 and are considered a bad sign for disease progression. However, less is known about IFN-α–specific autoantibodies in other tissues, such as the mucosa. Here, Babcock et al. used a multiparameter flow cytometry technique called FlowBEAT to show that IgA1 autoantibodies targeting IFN-α could be found in the nasal mucosa and were associated with improved responses to SARS-CoV-2. The induction of these anti–IFN-α autoantibodies was temporally linked to a decline in IFN-α itself, suggesting that elicitation of these autoantibodies may be a mechanism to temper inflammation in the respiratory mucosa. These data suggest that there is a complex, location-dependent, role for antibodies against IFN-α and that these antibodies may tip the balance between protection and pathology. —Courtney Malo [ABSTRACT FROM AUTHOR]