Hepatocellular carcinoma (HCC) is a highly heterogeneous disease. Reduced expression of focal adhesion is considered as an important prerequisite for tumor cell invasion and metastasis. However, the prognostic value of focal adhesion related genes in HCC remains to be further determined. In this study, RNA expression profiles were downloaded from public databases. A five focal adhesion related gene signature model was established by the least absolute shrinkage and selection operator Cox regression analysis, which categorized patients into high- and low-risk groups. Multivariate Cox regression analysis showed that the risk score was an independent predictor for overall survival. Single-sample gene set enrichment analysis revealed that immune status was different between the two risk groups, and tumor-related pathways were enriched in high-risk group. The risk score was significantly associated with tumor grade, tumor stage, immune scores, and immune infiltrate types. Pearson correlation showed that the expression level of prognostic genes was associated with anti-tumor drug sensitivity. Besides, the mRNA and protein expression of prognostic genes was significantly different between HCC tissues and adjacent non-tumorous tissues in our separate cohort. Taken together, a novel focal adhesion related gene signature can be used for prognostic prediction in HCC, which may be a therapeutic alternative.