OBJECTIVES: We hope to identify key molecules that can be used as markers of asthma severity and investigate their correlation with immune cell infiltration in severe asthma. METHODS: An asthma dataset was downloaded from the Gene Expression Omnibus database and then processed by R software to obtain differentially expressed genes (DEGs). First, multiple enrichment platforms were applied to analyze crucial biological processes and pathways and protein-protein interaction networks related to the DEGs. We next combined least absolute shrinkage and selection operator logistic regression and the support vector machine-recursive feature elimination algorithms to screen diagnostic markers of severe asthma. Then, a local cohort consisting of 40 asthmatic subjects (24 with moderate asthma and 16 with severe asthma) was used for biomarker validation. Finally, infiltration of immune cells in asthma bronchoalveolar lavage fluid and their correlation with the screened markers was evaluated by CIBERSORT. RESULTS: A total of 97 DEGs were identified in this study. Most of these genes are enriched in T cell activation and immune response in the asthma biological process. CC-chemokine receptor 7 (CCR7) and natural killer cell protein 7(NKG7) were identified as markers of severe asthma. The highest area under the ROC curve (AUC) was from a new indicator combining CCR7 and NKG7 (AUC = 0.851, adj. p < 0.05). Resting and activated memory CD4 T cells, activated NK cells, and CD8 T cells were found to be significantly higher in the severe asthma group (adj. p < 0.01). CCR7 and NKG7 were significantly correlated with these infiltrated cells that showed differences between the two groups. In addition, CCR7 was found to be significantly positively correlated with eosinophils (r = 0.38, adj. p < 0.05) infiltrated in bronchoalveolar lavage fluid. CONCLUSION: CCR7 and NKG7 might be used as potential markers for asthma severity, and their expression may be associated with differences in immune cell infiltration in the moderate and severe asthma groups.