To explore the value of Krüppel-like factor 5 (KLF5), a family member of the zinc finger protein transcription factor, in the diagnosis and prognostic evaluation of hepatocellular carcinoma (HCC). Cancerous and non-cancerous tissues were collected from 126 cases after HCC surgery by self-matching method with microarray fabrication. Immunohistochemistry was used to analyze the expression of KLF5, clinicopathological characteristics and prognostic value. The sera of 222 cases with chronic liver disease were collected and their KLF5 levels were quantitatively determined by enzyme-linked immunosorbent assay (ELISA). Simultaneously, 40 normal human sera were used as controls to evaluate the value of abnormal KLF5 in the diagnosis and differentiation of benign and malignant liver diseases. T-test, Z-test and χ (2) test were performed on the data. The positive expression rate of KLF5 in the HCC group was 95.2% (120/126), which was significantly higher than the non-cancerous group 38.9% (49/126; χ (2) = 14.385, < 0.0