The IRF family of proteins involves in the tumor progression. However, but the functions of IRF5 in the tumorigenesis are largely unknown. Here, IRF5 was found to be up-regulated in hepatocellular carcinoma (HCC). Interfering with IRF5 inhibited the growth and tumorigenic ability of HCC cells. When studying the molecular mechanism, it was found that TRIM35 interacted with IRF5, promoting the ubiquitination and degradation of IRF5. In the clinical specimens of HCC, TRIM35 was negatively correlated with the expression of IRF5. These observations reveal the oncogenic function of IRF5 in the progression of HCC, suggesting that IRF5 is a promising target for the therapy of HCC.