Most of COVID-19 patients have a mild disease course, while approximately 20% have moderate to severe disease. T cell-mediated immunity is crucial for protection against severe COVID-19. By investigating a perceived increased rate of indeterminate QuantiFERON-TB Gold Plus results in hospitalized COVID19 patients, we found that a big portion of severely ill COVID-19 patients’ peripheral T cells were unable to produce measurable IFN-g when stimulated with phytohemagglutinin (PHA), a potent IFN-g mitogen, reflected by an indeterminate QuantiFERON-TB Gold Plus result. We further performed the deep-proteomic of 52 serum samples from 52 COVID-19 patients and 30 matched healthy controls. The results indicated several pathways such as hypertrophic cardiomyopathy, dilated cardiomyopathy pathways, complement and coagulation cascade, and T cell differentiation related to IFN-g indeterminate. These data provide evidence that many of these patients demonstrate a focused Th2 immune response with inhibition of IFN-g signaling and, in many cases, significant elevations of IL-6.