Cirrhosis is the primary driver of hepatocellular carcinoma (HCC). Blocking the deterioration of cirrhosis into HCC would be of benefit for long–term survival. We applied a series of bioinformatic online databases to select and analyze the hub genes concerning cirrhosis and HCC, and identified UBE2T and CYP3A4 as hub genes for cirrhosis-HCC transformation. An elevated UBE2T and a decreased CYP3A4 were expressed in HCC compared with cirrhosis, which have been confirmed by real-time polymerase chain reaction (RT–PCR), Western Blotting (WB) and immunohistochemistry (IHC). The specificity (89.9%) and sensitivity (74.1%) on the combination of UBE2T and CYP3A4 for predicting HCC development in cirrhosis patients were better than that of UBE2T or CYP3A4 alone, or alpha-fetoprotein. The effectiveness of the combination of UBE2T and CYP3A4 was further verified by 15 paired HCC and paracancerous cirrhosis samples using RT–PCR, with a specificity of 100% and a sensitivity of 80%. HCC patients with elevated UBE2T and decreased CYP3A4 expression demonstrated a poorer overall survival rate (P = 0.0016, 0.019) and disease-free survival rate (P = 0.0013, 0.041). In conclusion, UBE2T and CYP3A4 could be a new combination of biomarkers for the carcinogenesis and progression of cirrhosis into HCC.