Background: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by recurrent abdominal pain associated with altered bowel habits, with a higher prevalence in females. While most transcriptomic studies have focused on gut mucosal biopsies, less is known about systemic transcriptional differences. This study aimed to investigate sex-specific whole-blood transcriptome profiles in IBS. Whole-blood RNA sequencing was performed on 21 IBS patients and 14 healthy controls using DNBSEQ-G400 platform, generating ~ 20M reads/sample. Differential expression analysis was conducted separately for females (IBS n = 16, controls n = 8) and males (IBS n = 5, controls n = 6), using DESeq2 (adj. p < 0.05). Functional enrichment and protein–protein interaction (PPI) analyses were performed using STRING-db. Transcriptome analysis revealed sex-specific transcriptomic signatures. In females, 139 differentially expressed genes (DEGs) were upregulated and 150 were downregulated in IBS compared with controls. These DEGs were enriched for pathways associated with antiviral defense, interferon signaling, and innate immune activation. In males, 17 DEGs were upregulated and 26 were downregulated, with enrichment pointing toward neutrophil-related responses and antibacterial pathways. PPI network analysis identified sex-specific genes: suppressed interferon-stimulated genes (e.g., IFI44L and RSAD2) in females, and neutrophil granule-associated genes (e.g., CEACAM8, DEFA4, LTF) in males. Whole-blood transcriptome profiling reveals distinct immune-related signatures in IBS that differ between females and males.