Objective: The study aims to explore the prognostic significance of zona pellucida glycoprotein 3 (ZP3) in hepatocellular carcinoma (HCC) tissues. Methods: The expression of ZP3 protein in HCC tissues was detected by immunohistochemistry (IHC) to study its effects on the clinicopathological characteristics and prognosis of HCC patients. The Cancer Genome Atlas (TCGA) database was used to confirm the expression of ZP3 in HCC tissues and Gene set enrichment analysis (GSEA) was performed to obtain potential ZP3-related pathways in HCC. Results: IHC detection found that ZP3 had a high expression in HCC tissues and was associated with cirrhosis, and hepatitis B virus infection of HCC patients (P<0.05). TCGA database also showed that ZP3 was up-regulated in HCC tissues. Further survival evaluation confirmed that ZP3 expression caused an impact on the overall survival time and disease-free survival time of HCC patients (P<0.05), implying a potential role in HCC prognosis. GSEA analysis indicated that the 187 differential gene sets were mainly involved in 10 signaling pathways, including 5 up-regulated and 5 down-regulated pathways. Conclusion: High expression of ZP3 in HCC tissues shows an important role in HCC development and prognosis.