Background: Coiled coil domain containing protein 51 (CCDC51), as the two transmembrane helical domains protein, little is known about the function of it in human cancer. Methods: TCGA, GEPIA, cBioPortal, GTEx, and TIMER were employed to analyze expression, immune cells infiltration, prognostic value, genetic alteration, cancer patients’ mutation burden, stem cell stability, and microsatellite instability of CCDC51 . Results: Decreased CCDC51 expression significantly related with poor overall survival (OS) of acute myeloid leukemia (LAML), adrenocortical carcinoma (ACC), glioma (GBMLGG), kidney chromophobe (KICH), liver hepatocellular carcinoma (LIHC), lung squamous cell carcinoma (LUSC), skin cutaneous melanoma (SKCM) and uveal melanoma (UVM), lung adenocarcinoma (LUAD), disease-specific survival (DSS) of ACC, GBMLGG, SKCM and UVM, and progression-free interval (PFI) of ACC, KICH and pancreatic adenocarcinoma, squamous cell carcinoma of the head and neck (HNSC). In human cancer, immune cell infiltration, and tumor microenvironment, CCDC51 expression is associated with MSI, RNA modifications, and diverse cancer drug sensitivity. There is potential for it to be an independent factor contributing to OS in LIHC. CCDC51 was an independent factor for LIHC prognosis in Cox regression and nomogram analysis. The results of the the Kyoto Encyclopedia of Genes and Gene Ontology and Genomes indicated that CCDC51 was involved in aminoacyl-tRNA biosynthesis, RNA transport, colorectal cancer, Wnt signaling pathway, mismatch repair, mitochondrion, pseudo uridine synthase activity, mRNA processing, mitochondrial matrix, regulation of mRNA stability, and mitochondrial inner membrane. Conclusion: Our research can provide new-insights for LIHC prognostic biomarkers of CCDC51.