Although most severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–infected individuals experience mild coronavirus disease 2019 (COVID-19), some patients suffer from severe COVID-19, which is accompanied by acute respiratory distress syndrome and systemic inflammation. To identify factors driving severe progression of COVID-19, we performed single-cell RNA sequencing using peripheral blood mononuclear cells (PBMCs) obtained from healthy donors, patients with mild or severe COVID-19, and patients with severe influenza. Patients with COVID-19 exhibited hyperinflammatory signatures across all types of cells among PBMCs, particularly up-regulation of the tumor necrosis factor/interleukin-1β (TNF/IL-1β)–driven inflammatory response as compared with severe influenza. In classical monocytes from patients with severe COVID-19, type I interferon (IFN) response coexisted with the TNF/IL-1β–driven inflammation, and this was not seen in patients with milder COVID-19. We documented type I IFN–driven inflammatory features in patients with severe influenza as well. On the basis of this, we propose that the type I IFN response plays a pivotal role in exacerbating inflammation in severe COVID-19.