Aim To investigate the molecular mechanism of interaction between rheumatoid arthritis (RA) and atherosclerosis (As) based on bioinformatics analysis. Methods The gene expression profiles of As and RA were downloaded from GEO database, differentially expressed genes between RA and As were identified through the test sets, the biological function of common differentially expressed genes was studied by enrichment analysis. Cytoscape software was used to construct the differentially expressed gene protein-protein interaction network and screen the hub genes. Transcriptional regulatory relationship revealed by the TRRUST database predicts transcription factors. Transcription factors were validated by test sets, and hub genes were validated by validation sets and blood samples. Results A total of 198 differentially expressed genes were identified. Functional enrichment analysis showed that differentially expressed genes were mainly concentrated in signaling pathways regulated by cytokines, leukocyte migration, positive regulation of leukocytes, and interaction between cytokines and cytokine receptors. Cytoscape demonstrated the differentially expressed genes and gene clustering modules, obtained the hub genes CCL5, CCR1, CCR2, CCR5, IRF8, ITGAM, ITGB2, LCP2, NCF2 and PTPRC, and the results of validation sets showed that the genes were reliable. qPCR results showed that the expression levels of CCR1 and IRF8 in patients with As combined with RA were significantly higher than those in healthy people. Conclusion The regulatory effect of CCR1 and IRF8 is likely to be the hub factor of RA merging with As.