While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients1-3, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a whole-blood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferon-stimulated gene (ISG) expression3 across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies that functionally block the production of the mild disease-associated ISG-expressing cells, by engaging conserved signaling circuits that dampen cellular responses to interferons. Overzealous antibody responses pit the immune system against itself in many COVID-19 patients and perhaps in other viral infections and this study defines targets for immunotherapies in severe patients to re-engage viral defense.