BACKGROUND: Clear Cell Renal Cell Carcinoma (CCRCC) is the most aggressive subtype of Renal Cell Carcinoma (RCC) with high metastasis and recurrence rates. This study aims to find new potential key genes of CCRCC. METHODS: Four gene expression profiles (GSE12606, GSE53000, GSE68417, and GSE66272) were downloaded from the Gene Expression Omnibus (GEO) database. The TCGA KIRC data was downloaded from The Cancer Genome Atlas (TCGA). Using GEO2R, the differentially expressed genes (DEG) in CCRCC tissues and normal samples were analyzed. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed in DAVID database. A protein-protein interaction (PPI) network was constructed and the hub gene was predicted by STRING and Cytoscape. GEPIA and Kaplan-Meier plotter databases were used for further screening of Key genes. Expression verification and survival analysis of key genes were performed using TCGA database, GEPIA database, and Kaplan-Meier plotter. Receiver operating characteristic (ROC) curve was used to analyze the diagnostic value of key genes in CCRCC, which is plotted by R software based on TCGA database. UALCAN database was used to analyze the relationship between key genes and clinical pathology in CCRCC and the methylation level of the promoter of key genes in CCRCC. RESULTS: A total of 289 up-regulated and 449 down-regulated genes were identified based on GSE12606, GSE53000, GSE68417, and GSE66272 profiles in CCRCC. The upregulated DEGs were mainly enriched with protein binding and PI3K-Akt signaling pathway, whereas down-regulated genes were enriched with the integral component of the membrane and metabolic pathways. Next, the top 35 genes were screened out from the PPI network according to Degree, and three new key genes ITGAX, LAPTM5 and SERPINE1 were further screened out through survival and prognosis analysis. Further results showed that the ITGAX, LAPTM5, and SERPINE1 levels in CCRCC tumor tissues were significantly higher than those in normal tissues and were associated with poor prognosis. ROC curve shows that ITGAX, LAPTM5, and SERPINE1 have good diagnostic value with good specificity and sensitivity. The promoter methylation levels of ITGAX, LAPTM5 and SERPINE1 in CCRCC tumor tissues were significantly lower than those in normal tissues. We also found that key genes were associated with clinical pathology in CCRCC. CONCLUSION: ITGAX, LAPTM5, and SERPINE1 were identified as novel key candidate genes that could be used as prognostic biomarkers and potential therapeutic targets for CCRCC.