Interferon-gamma release assays are used to screen various patient populations for latent tuberculosis infection. In this issue of the Journal of Clinical Microbiology, Ward et al. (J Clin Microbiol 59:e00811-21, 2021, https://doi.org/10.1128/JCM.00811-21) investigated an increased indeterminate rate in the QuantiFERON-TB Gold Plus assay among COVID-19 patients that was independent of immunosuppressive agents and lymphopenia. In their study, COVID-19 patients with indeterminate QuantiFERON-TB Gold Plus results trended toward decreased survival as well as increased serum IL-6 and IL-10 levels, though the differences were not statistically significant. They suggest that this pattern of cytokine expression supports an impairment of Th1, and specifically interferon-gamma production, in critically ill COVID-19 patients, as indicated by indeterminate QuantiFERON-TB Gold Plus results. Clinicians should be aware of the increased rate of indeterminate QuantiFERON-TB Gold Plus results in critically ill COVID-19 patients.