The upregulation of cell division cycle associated protein 5 (CDCA5) has been observed in various cancer types. However, the prognostic value of CDCA5 and its underlying mechanism contributing to tumorigenesis in hepatocellular carcinoma (HCC) remain poorly understood. We used tissue microarray (TMA) to evaluate the prognosis of 304 HCC samples based on their CDCA5 expression, and analyzed the genomic features correlated with CDCA5 by using dataset from The Cancer Genome Atlas (TCGA). Compared with adjacent normal tissues, increased expression of CDCA5 was found in HCC tissues. Moreover, higher expression of CDCA5 was associated with inferior OS and DFS outcomes in HCC patients. The enrichment plots showed that the gene signatures in cell cycle, DNA replication and p53 pathways were enriched in patients with higher CDCA5 expression. Meanwhile, statistically higher mutations burdens in TP53 could also be observed in CDCA5-high patients. Integrative analysis based on miRNAseq and methylation data demonstrated a potential association between CDCA5 expression and epigenetic changes. In conclusion, our study provided the evidence of CDCA5 as an oncogenic promoter in HCC and the potential function of CDCA5 in affecting tumor microenvironment.