Coronavirus disease (COVID-19) caused by SARS-CoV-2 virus is associated with a wide range of clinical manifestations, including autoimmune features and autoantibody production in a small subset of patients. Pre-exiting neutralizing autoantibodies against type I interferons (IFNs) are associated with COVID-19 disease severity. In this case report, plasma levels of IgG against type I interferons (IFNs) were increased specifically among the 103 autoantibodies tested following the second shot of COVID-19 vaccine BNT162b2 compared to pre-vaccination and further increased following the third shot of BNT162b2 in a healthy woman. Unlike COVID-19 mediated autoimmune responses, vaccination in this healthy woman did not induce autoantibodies against autoantigens associated with autoimmune diseases. Importantly, IFN-α-2a-induced STAT1 responses in human PBMCs in vitro were suppressed by adding plasma samples from the study subject post- but not pre-vaccination. After the second dose of vaccine, the study subject exhibited severe dermatitis for about six months and responded to treatments with Betamethasone Dipropionate Ointment and antihistamines for about one month. Immune responses to type I IFN can be double-edged swords in enhancing vaccine efficacy and immune responses to infectious diseases, as well as accelerating chronic disease pathogenesis (e.g., chronic viral infections and autoimmune diseases). This case highlights the BNT162b2-induced neutralizing anti-type I IFN autoantibody production, which may affect immune functions in a small subset of general population and patients with some chronic diseases.