BACKGROUND: Clinical observations have shown that many patients with ischemic stroke (IS) have a history of obstructive sleep apnea (OSA) both before and after the stroke's onset, suggesting potential underlying connections and shared comorbid mechanisms between the two conditions. The aim of this study is to identify the genetic characteristics of OSA patients who develop IS and to establish a reliable disease diagnostic model to assess the risk of IS in OSA patients. METHODS: We selected IS and OSA datasets from the Gene Expression Omnibus (GEO) database as training sets. Core genes were identified using the Limma package, Weighted Gene Co-expression Network Analysis (WGCNA), and machine learning algorithms. Gene Set Variation Analysis (GSVA) was conducted for pathway enrichment analysis, while single-sample gene set enrichment analysis (ssGSEA) was employed for immune infiltration analysis. Finally, a diagnostic model was developed using Least Absolute Shrinkage and Selection Operator (LASSO) regression, with its diagnostic efficacy validated using receiver operating characteristic (ROC) curves across two independent validation sets. RESULTS: The results revealed that differential analysis and machine learning identified two common genes, TM9SF2 and CCL8, shared between IS and OSA. Additionally, seven signaling pathways were found to be commonly upregulated in both conditions. Immune infiltration analysis demonstrated a significant decrease in monocyte levels, with TM9SF2 showing a negative correlation and CCL8 showing a positive correlation with monocytes. The diagnostic model we developed exhibited excellent predictive value in the validation set. CONCLUSIONS: In summary, two immune-related core genes, TM9SF2 and CCL8, were identified as common to both IS and OSA. The diagnostic model developed based on these genes may be used to predict the risk of IS in OSA patients.