In response to acute infection, there is a metabolic switch toward ketogenesis and the production of ketone bodies, including β-hydroxybutyrate (BHB). In Nature, Karagiannis et al. show that impaired ketogenesis is linked to T cell dysfunction in severe COVID-19. Patients infected with influenza virus have more serum BHB than that of healthy people, but patients infected with SARS-CoV-2 do not. When CD4+ T cells are cultured with BHB, interferon-γ (IFNγ) production is increased and BHB acts as an alternative carbon source to fuel oxidative phosphorylation. Supplementing mice with BHB increases the number of IFNγ+ CD4+ T cells, which reprograms CD4+ T cells toward oxidative phosphorylation and diminishes their glycolytic capacity. When mice infected with SARS-CoV-2 are given BHB, there is increased IFNγ production, viral clearance and survival. Thus, impaired ketogenesis may have a role in severe COVID-19.