Background: Infection can induce granulopoiesis. This process potentially gives rise to blood gene classifiers of sepsis in systemic inflammatory response syndrome (SIRS) patients. The aim of this study was to identify sepsis signature genes in blood granulocytes from patients with sepsis and SIRS on intensive care unit (ICU) admission. Methods: CD15+ cells encompassing all stage of terminal granulocytic differentiation were analyzed. CD15 transcriptomes from patients with sepsis and SIRS on ICU admission and presurgical controls (discovery cohort) were subjected to differential gene expression and pathway enrichment analyses. Differential expression was validated by bead array in independent sepsis and SIRS patients (validation cohort). We referred to the GeneCards database for subcellular gene associations and Grassi et al. (Cell Rep 2018; 24: 2784-2794) for granule signature genes. Blood counts of granulocyte precursors were determined by flow cytometry in a validation cohort subset. Results: Despite similar transcriptional CD15 responses in sepsis and SIRS, enrichment of pathways known to decline at the metamyelocyte stage (mitochondrial, lysosome, cell cycle, proteasome) was associated with sepsis but not SIRS. Twelve of 30 validated genes, from 100 selected for changes in response to sepsis rather than SIRS, were endo-lysosomal. Revisiting the discovery transcriptomes revealed elevated expression of promyelocyte-restricted azurophilic granule genes in sepsis and myelocyte-restricted specific granule genes in sepsis followed by SIRS. Blood counts of promyelocytes and myelocytes were higher in sepsis than SIRS. Conclusions: Sepsis-induced granulopoiesis and signature genes of early terminal granulocytic differentiation provide a rationale for classifiers of sepsis in patients with SIRS on ICU admission. Yet, distinction of this process from non-infectious tissue injury-induced granulopoiesis remains to be investigated.