Intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD) is a complex disease, leading to the damage of multiple systems. The pathogen that triggers this sophisticated disease is still unknown. The aim of this study was to identify gene signatures during IVIG-resistant KD and uncover their potential mechanisms. The gene expression profiles of GSE18606 were downloaded from the GEO database. The GSE18606 dataset contained eight IVIG-resistant KD samples and nine healthy age-appropriate controls. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed, and protein-protein interaction (PPI) network of the differentially expressed genes (DEGs) was constructed by Cytoscape software. In total, 73 DEGs were identified in IVIG-resistant KD, including 58 upregulated genes and 15 downregulated genes. GO analysis results showed that DEGs were significantly enriched in biological processes of neutrophil degranulation, neutrophil mediated immunity, and neutrophil activation involved in immune response. Among them, 10 hub genes (S100A8, S100A9, S100A12, HGF, LCN2, LY96, CTGF, MMP8, IRAK3, and SLPI) with a high degree of connectivity were selected. The present study indicated that the identified DEGs and hub genes promote our understanding of the molecular mechanisms underlying the development of IVIG-resistant KD, and might be used as molecular targets and diagnostic biomarkers for the treatment of IVIG-resistant KD.