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AIM: To investigate the prevalence and time of Dickkopf (DKK) family methylation and its clinical significance in hepatocarcinogenesis.METHODS: Methylation of DKK family genes was quantitatively analyzed in 115 liver tissue samples, including 50 pairs of primary hepatocellular carcinoma (HCC) and matched noncancerous cirrhotic tissue samples, as well as 15 liver cirrhosis biopsy samples.RESULTS: The methylation level of DKK3 was significantly higher in HCC tissue samples than in matched noncancerous cirrhotic tissue samples ( P < 0.0001) or in liver cirrhosis biopsy samples ( P = 0.0139).Receiver operator characteristic curve analysis confirmed that the percent of methylated reference (PMR) values of DKK3 could effectively discriminate HCC tissue samples from noncancerous tissue samples (AUC = 0.8146) or liver cirrhosis biopsy samples (AUC = 0.7093).Kaplan-Meier survival curves revealed that the progression-free survival time of patients with a higher DKK3 methylation level (PMR > 1%) was significantly shorter than that of those with a lower DKK3 methylation level (PMR ≤ 1%) ( P = 0.0255).Multivariate Cox analysis indicated that methylated DKK3 was significantly and independently related with a shorter survival time (relative risk = 2.527, 95% CI: 1.063-6.008, P = 0.036) of HCC patients.CONCLUSION: Methylation of DKK3 is an important event in early malignant transformation and HCC progression, and therefore might be a prognostic indicator for risk assessment of HCC.