Abstract: Objective To investigate the changes in retinal transcriptome profile of mice with endotoxin-induced uveitis (EIU) following dexamethasone (DEX) treatment and explore the mechanisms underlying the therapeutic effect of DEX. Methods EIU was induced in BALB/c mice by intravitreal injection of 125 ng lipopolysaccharide (LPS), followed by topical application of DEX (0.1%) eye drops every 4 h for 24 h. The anterior chamber inflammation was examined with a slit lamp and the clinical scores were assessed. The morphological changes in the eyes were assessed at 24 h after LPS injection. The retinas were harvested for analysis of transcriptome profile using the next-generation sequencing (NGS)-based RNA sequencing (RNA-seq), and the expressions of the inflammatory cytokines and the differentially expressed genes (DEGs) were verified using real-time PCR. Results DEX alleviated the inflammatory response and reduced the mRNA expressions of IL-6, TNF-α, MCP-1 and ICAM-1 at 24 h after LPS injection. A total of 52 DEGs were identified by RNA-seq. Within these DEGs, 37 genes were upregulated and 15 genes were down-regulated in LPS group as compared with DEX+LPS group. No significantly enriched Gene Ontology (GO) terms was noted. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed 6 up-regulated and 2 down-regulated KEGG pathways. RIG-I-like receptor signaling pathway and several immune- and inflammation-related genes including Ifit1, H2-T24, Mx2 and Eif2ak2 were significantly down regulated by DEX. Verification with RT-PCR yielded results consistent with these findings. Conclusion DEX alleviates LPS-induced inflammatory response in the retina of mice, and such protective effect is probably mediated by RIG-I like receptor signal pathway and the immune-and inflammation-related genes.