Iron metabolism is considered to play the principal role in sepsis, but the key iron metabolism-related genetic signatures are unclear. In this study, we analyzed and identified the genetic signatures related to the iron-metabolism in sepsis by using a bioinformatics analysis of four transcriptomic datasets from the GEO database. A total of 21 differentially expressed iron metabolism-related signatures were identified including 9 transporters, 8 enzymes, and 4 regulatory factors. Among them, lipocalin 2 was found to have the highest diagnostic value as its expression showed significant differences in all the comparisons including sepsis vs healthy controls, sepsis vs non-sepsis diseases, and mild forms vs severe forms of sepsis. Besides, the cytochrome P450 gene CYP1B1 also showed diagnostic values for sepsis from the non-sepsis diseases. The CYP4V2, LTF, and GCLM showed diagnostic values for distinguishing the severe forms from mild forms of sepsis. Our analysis identified 21 sepsis-associated iron metabolism-related genetic signatures, which may represent diagnostic and therapeutic biomarkers of sepsis, and will improve our understanding of the molecular mechanism underlying the occurrence of sepsis.© 2023 the author(s), published by De Gruyter.