Background. Chromobox protein homolog 8 (CBX8), a transcriptional repressor, participates in many biological processes in various carcinomas. Cell differentiation, aging, and cell cycle progression are examples of such processes. It is critical to investigate CBX8 expression and its relationship with clinicopathological characteristics in liver hepatocellular carcinoma (LIHC), kidney renal clear cell carcinoma (KIRC), and ovarian cancer (OV) to investigate CBX8’s potential diagnostic and prognostic values. Methods. TCGA and CPTAC databases were used to compare the data between cancer and matched normal tissues on RNA and protein expression profiles and their relevant clinical information to determine the relationship between CBX8 and clinicopathological features. Kaplan–Meier analyses were used to assess CBX8 relationship’s with disease-free survival (DFS), relapse-free survival (RFS), and overall survival (OS). The multivariate Cox regression analysis was used to identify independent risk factors which affect prognosis. DNA methylation and genetic changes and their impact on prognoses were evaluated by cBioPortal and MethSurv websites. Spearman’s correlation was used to determine the relationship of CBX8 expression with somatic mutation. Tumor immune estimation resource (TIMER) was adopted to investigate the relationship between CBX8 and immune cell infiltration (ICI). CBX8-relevant genes and proteins are analyzed by EnhancedVolcano and STRING databases. The gene set enrichment analysis (GSEA) was performed to investigate the potential functions of CBX8. Results. CBX8 RNA and protein overexpression were confirmed in LIHC, KIRC, and OV (