Despite the high incidence of COVID-19 worldwide, clinical experience with severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) in inborn errors of immunity remains limited. Recent studies have shown that patients with defects in type 1 interferon (IFN)-related pathways or those with autoantibodies against type 1 IFNs develop severe COVID-19. We reported the clinical course of 22 patients with CTLA-4 insufficiency and COVID-19 and retrospectively examined autoantibodies against type 1 IFNs at baseline. Data were obtained from the patient interviews and chart reviews. Screening for anti-IFN autoantibodies was performed using a multiplex particle-based assay. Student t test, Mann Whitney, analysis of variance, or χ2 tests were used where appropriate. Twenty-two patients aged from 8 months to 54 years, with genetically confirmed CLTA-4 insufficiency, developed COVID-19 from 2020 to 2022. The most common symptoms were fever, cough, and nasal congestion, and the median duration of illness was 7.5 days. Twenty patients (91%) developed mild COVID-19 and were treated as outpatients. Two patients were hospitalized because of COVID-19 pneumonia but did not require mechanical ventilation. Ten (45%) patients were vaccinated at the time of their first COVID-19 infection. Eleven patients received outpatient treatment with monoclonal antibodies against the SARS-CoV-2 spike protein. During the study period, 17 patients were vaccinated against SARS-CoV-2, with no severe vaccine-related adverse effects. Although median anti-S titers following vaccination or infection were lower in patients receiving immunoglobulin replacement therapy (IGRT) (349 IU/dL) than in those not receiving IGRT (2594 IU/dL; P = .15); 3 of 9 patients on IGRT developed titers >2000 IU/dL. All patients tested negative for autoantibodies against IFN-α, IFN-β, and IFN-ω at baseline. Most patients with CTLA-4 insufficiency and COVID-19 had nonsevere disease, lacked autoantibodies against type 1 IFNs, and tolerated messenger RNA vaccines with few adverse effects. Whether our findings can be extrapolated to patients receiving CTLA-4-targeting checkpoint inhibitors requires further studies.