METHODS: The differentially expressed genes (DEGs) were identified using periodontitis-related microarray from the GEO database, and OS-genes were extracted from GeneCards database. The intersection of the OS-genes and the DEGs was considered as oxidative stress-related DEGs (OS-DEGs) in periodontitis. The Pearson correlation and protein-protein interaction analyses were used to screen key OS-genes. Gene set enrichment, functional enrichment, and pathway enrichment analyses were performed in OS-genes. Based on key OS-genes, a risk score model was constructed through logistic regression, receiver operating characteristic curve, and stratified analyses. RESULTS: In total, 74 OS-DEGs were found in periodontitis, including 65 upregulated genes and 9 downregulated genes. Six of them were identified as key OS-genes (CXCR4, SELL, FCGR3B, FCGR2B, PECAM1, and ITGAL) in periodontitis. All the key OS-genes were significantly upregulated and associated with the increased risk of periodontitis. Functional enrichment analysis showed that these genes were mainly associated with leukocyte cell-cell adhesion, phagocytosis, and cellular extravasation. Pathway analysis revealed that these genes were involved in several signaling pathways, such as leukocyte transendothelial migration and osteoclast differentiation. CONCLUSION: In this study, we screened six key OS-genes that were screened as risk factors of periodontitis. We also identified multiple signaling pathways that might play crucial roles in regulating oxidative stress damage in periodontitis. In the future, more experiments need to be carried out to validate our current findings.