BACKGROUND: Calcific aortic valve disease (CAVD) is one of the most prevalent valvular diseases and is the second most common cause for cardiac surgery. However, the mechanism of CAVD remains unclear. This study aimed to investigate the role of pyroptosis-related genes in CAVD by performing comprehensive bioinformatics analysis. METHODS: Three microarray datasets (GSE51472, GSE12644 and GSE83453) and one RNA sequencing dataset (GSE153555) were obtained from the Gene Expression Omnibus (GEO) database. Pyroptosis-related differentially expressed genes (DEGs) were identified between the calcified and the normal valve samples. LASSO regression and random forest (RF) machine learning analyses were performed to identify pyroptosis-related DEGs with diagnostic value. A diagnostic model was constructed with the diagnostic candidate pyroptosis-related DEGs. Receiver operating characteristic (ROC) curve analysis was performed to estimate the diagnostic performances of the diagnostic model and the individual diagnostic candidate genes in the training and validation cohorts. CIBERSORT analysis was performed to estimate the differences in the infiltration of the immune cell types. Pearson correlation analysis was used to investigate associations between the diagnostic biomarkers and the immune cell types. Immunohistochemistry was used to validate protein concentration. RESULTS: We identified 805 DEGs, including 319 down-regulated genes and 486 up-regulated genes. These DEGs were mainly enriched in pathways related to the inflammatory responses. Subsequently, we identified 17 pyroptosis-related DEGs by comparing the 805 DEGs with the 223 pyroptosis-related genes. LASSO regression and RF algorithm analyses identified three CAVD diagnostic candidate genes (TREM1, TNFRSF11B, and PGF), which were significantly upregulated in the CAVD tissue samples. A diagnostic model was constructed with these 3 diagnostic candidate genes. The diagnostic model and the 3 diagnostic candidate genes showed good diagnostic performances with AUC values >0.75 in both the training and the validation cohorts based on the ROC curve analyses. CIBERSORT analyses demonstrated positive correlation between the proportion of M0 macrophages in the valve tissues and the expression levels of TREM1, TNFRSF11B, and PGF. CONCLUSION: Three pyroptosis-related genes (TREM1, TNFRSF11B and PGF) were identified as diagnostic biomarkers for CAVD. These pyroptosis genes and the pro-inflammatory microenvironment in the calcified valve tissues are potential therapeutic targets for alleviating CAVD.