BACKGROUND: Osteoarthritis (OA) and rheumatoid arthritis (RA) are well-known cause of joint disability. Although they have shown the analogous clinical features involving chronic synovitis that progresses to cartilage and bone destruction, the pathogenesis that initiates and perpetuates synovial lesions between RA and OA remains elusive. OBJECTIVE: This study is aimed at identifying disease-specific hub genes, exploring immune cell infiltration, and elucidating the underlying mechanisms associated with RA and OA synovial lesion. METHODS: Gene expression profiles (GSE55235, GSE55457, GSE55584, and GSE12021) were selected from Gene Expression Omnibus for analysis. Differentially expressed genes (DEGs) were identified by the "LIMMA" package in Bioconductor. The DEGs were identified by Gene Ontology (GO) and KEGG pathway analysis. A protein-protein interaction network was constructed to identify candidate hub genes by using STRING and Cytoscape. Hub genes were identified by validating from GSE12021. Furthermore, we employed the CIBERSORT website to assess immune cell infiltration between OA and RA. Finally, we explored the correlation between the levels of hub genes and relative proportion of immune cells in OA and RA. RESULTS: We identified 68 DEGs which were mainly enriched in immune response and chemokine signaling pathway. Six hub genes with a cutoff of AUC > 0.80 by ROC analysis and relative expression of P < 0.05 were identified successfully. Compared with OA, the RA synovial tissues consisted of a higher proportion of 7 immune cells, whereas 4 immune cells were found in relatively lower proportion (P < 0.05). In addition, the levels of 6 hub genes were closely associated with relative proportion of 11 immune cells in OA and RA. CONCLUSIONS: We used bioinformatics analysis to identify hub genes and explored immune cell infiltration of immune microenvironment in synovial tissues. Our results should offer insights into the underlying molecular mechanisms of synovial lesion and provide potential target for immune-based therapies of OA and RA.