Background: Liver cancer (LC) is in the seventh most common cancer and the fourth largest cause of cancer deaths. Although significant progress has been made in the prevention and treatment of viral hepatitis; alcoholic liver disease, obesity and diabetes are now emerging as major causes for LC. Recently there has been increase in identification of biomarkers which can predict LC risk and disease progression, but the roles of HOMER3 gene in LC are not known. Methods: First the expression of HOMER3 between normal and tumor tissues was determined using The Cancer Genome Atlas (TCGA), Genetic Expression Omnibus (GEO) and protein atlas datasets. HOMER3 expression at different clinical stage and overall survival (OS) was also determined. The role of HOMER3 on OS in relation to cancer stage, hepatitis virus infection and alcohol intake was also determined. STRING database determined HOMER3 interaction network and TCGA was used to verify the correlation status, and the roles of the network genes on OS. The pathways enriched by HOMER3 were determined by Gene Set Enrichment Analysis (GSEA). Results: HOMER3 was significantly highly expressed in tumor tissues as compared to normal tissues. The expression of HOMER3 correlated positively with clinical stage, with highest expression in advanced stages (Stage 3 and 4), and high HOMER3 expression was associated with poor OS. HOMER3’ s high expression was associated with poor OS in advanced stage, alcohol intake, and in those negative of viral hepatitis infection. HOMER3 interacted with HOMER1, SHANK1, GRM5, GRM1, DLGAP1, SHANK2, DLG4, SHANK3, DLG2 and DLGAP4, with positive correlation to HOMER1, SHANK1, GRM5, GRM1, DLGAP1, DLG4 and DLGAP4 and negative correlation to SHANK2, SHANK3 and DLG2. HOMER1 and DLGAP4 high expression were associated with poor OS while SHANK2, SHANK3 and DLG2 high expression were associated with favorable OS. GRM5 and GRM1 high expression were associated with favorable OS despite being positively correlated with HOMER3. ECM receptor interaction and Notch signaling were the upregulated pathways while Metabolism of xenobiotics by cytochrome p450 and PPAR signaling were the downregulated pathways. Conclusions: HOMER3 may is have a role in liver cancer progression of which its targeting may improve LC outcome.