This study investigates the peripheral immune response in patients with severe COVID-19 using single-cell RNA sequencing (scRNA-seq). Seven hospitalized patients with COVID-19 and six healthy controls were analyzed. The results show significant changes in the composition and phenotype of peripheral immune cells, particularly in monocytes, T cells, and natural killer (NK) cells. Key findings include a heterogeneous interferon-stimulated gene signature, downregulation of HLA class II, and the presence of a developing neutrophil population that may differentiate from plasmablasts. The study also highlights that peripheral monocytes and lymphocytes do not express substantial amounts of pro-inflammatory cytokines, suggesting that these cells are not major contributors to the cytokine storm in COVID-19. The findings provide insights into the immunopathology of severe COVID-19 and contribute to the understanding of the immune response to the virus.This study investigates the peripheral immune response in patients with severe COVID-19 using single-cell RNA sequencing (scRNA-seq). Seven hospitalized patients with COVID-19 and six healthy controls were analyzed. The results show significant changes in the composition and phenotype of peripheral immune cells, particularly in monocytes, T cells, and natural killer (NK) cells. Key findings include a heterogeneous interferon-stimulated gene signature, downregulation of HLA class II, and the presence of a developing neutrophil population that may differentiate from plasmablasts. The study also highlights that peripheral monocytes and lymphocytes do not express substantial amounts of pro-inflammatory cytokines, suggesting that these cells are not major contributors to the cytokine storm in COVID-19. The findings provide insights into the immunopathology of severe COVID-19 and contribute to the understanding of the immune response to the virus.