Abstract Background Hepatocellular carcinoma (HCC) is a malignancy causing highly death rate in the world. Despite the development of treatment strategies for HCC, prognosis of this malignancy remains unsatisfactory. In this study, we aimed to identify the target genes associated with the prognosis of HCC patients. Methods Three expression profiles of HCC tissues were extracted from the Gene Expression Omnibus database to explore the differentially expressed genes (DEGs) using GEO2R method. Functional enrichment analysis was performed to reveal the biological characteristics of DEGs. Protein-protein interaction (PPI) network was constructed using Cytoscape software. The survival curve of identified DEGs were tested by Kaplan-Meier analysis. Results We identified 15 DEGs (CYP39A1, CYR61, FOS, FOXO1, GADD45B, ID1, IL1RAP, MT1M, PHLDA1, RND3, SDS, SOCS2, TAT, S100P, and SPINK1) in HCC tissues. Prognosis analysis showed that 4 DEGs (FOXO1,SPINK1༌SOCS2, and TAT) correlated with overall survival time of HCC patients, which might serve as therapeutic targets for HCC patients. Conclusions By integrated bioinformatics analysis, we proposed a novel way to reveal key genes that closely relate to HCC development.