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Pregnancy zone protein (PZP), a member of the proteinase inhibitor I39 (‐2‐macroglobulin) family of proteins, is involved in the initiation and development of various tumors. The gene encoding PZP is hypermethylated and expressed at low levels in hepatocellular carcinoma (HCC) tissue and cells, but the function of PZP in HCC cells remains unclear. Here, we analyzed DNA methylation and mRNA expression of HCC in The Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset. We identified 10 methylation‐driven genes, of which PZP was significantly hypermethylated and poorly expressed in tumor tissue. We confirmed that PZP is highly methylated and poorly expressed in HCC cell lines via quantitative real‐time PCR experiment and methylation‐specific PCR. Furthermore, PZP markedly inhibited the proliferation, invasion and migration of HCC cells. These findings may provide a basis for exploring novel therapeutic targets for HCC.