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COVID-19 is associated with a wide spectrum of disease presentation, ranging from asymptomatic infection to acute respiratory distress syndrome (ARDS). Paradoxically, a direct relationship has been suggested between COVID-19 disease severity and the levels of circulating SARS-CoV-2-specific antibodies, including virus neutralizing titers. A serological analysis of 536 convalescent healthcare workers reveal that SARS-CoV-2-specific and virus-neutralizing antibody levels are elevated in individuals that experience severe disease. The severity-associated increase in SARS-CoV-2-specific antibody is dominated by IgG, with an IgG subclass ratio skewed towards elevated receptor binding domain (RBD)- and S1-specific IgG3. In addition, individuals that experience severe disease show elevated SARS-CoV-2 specific antibody binding to the inflammatory receptor FcɣRIIIa. Based on these correlational studies, we propose that Spike-specific IgG subclass utilization may contribute to COVID-19 disease severity through potent Fc-mediated effector functions. These results may have significant implications for SARS-CoV-2 vaccine design and convalescent plasma therapy., Graphical Abstract, In a serological analysis of convalescent healthcare workers, Yates et al. explore antibody profiles associated with COVID-19 severity. Their analysis reveals an IgG subclass ratio skewed toward IgG3 that correlates with COVID-19 disease severity. The authors hypothesize a link between IgG3, Fc effector functions, and inflammation characteristic of severe COVID-19.