GSDM family is a group of critical proteins that mediate pyroptosis and plays an important role in cell death and inflammation. However, their specific function in clear cell renal cell carcinoma (ccRCC, KIRC) have not been clarified comprehensively. In this study, we assessed the roles of the GSDM family in expression, prognostic value, functional enrichment analysis, genetic alterations, immune infiltration and DNA methylation in ccRCC patients by using different bioinformatics databases. We found that the expression levels of GADMA-E were significantly higher in ccRCC tissues compared with normal tissues, while the expression level of PJVK was decreased. Moreover, survival analysis indicated that upregulation of GSDME was related to poor overall survival (OS) and recurrence-free survival (RFS) of ccRCC patients. The main function of differentially expressed GSDM homologs was related to ion transport. We also found that the expression profiles of the GSDM family were highly correlated with infiltrating immune cells (i.e., CD8+ T cells, CD4+ T cells, B cells, macrophages, neutrophils and dendritic cells), and there were significant differences in the expression of GSDM family in different ccRCC immune subtypes. Furthermore, DNA methylation analysis indicated that the DNA methylation levels of GSDMA/B/D/E were decreased, while the DNA methylation level of PJVK was increased. In conclusion, this study provides integrated information about abnormal GSDM family members as potential biomarkers for the diagnosis and prognosis of ccRCC. Especially, GSDME was a potential clinical target and prognostic biomarkers for patients with ccRCC.