Background: Hepatocellular carcinoma (HCC) is a prevalent lethal cancer that remains challenging to treat. Therefore, investigation of novel targets and therapeutic strategies is essential. The role of ZBED4 in cancer remains unclear. Methods: Data were sourced from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), International Cancer Genome Consortium (ICGC), and Genomics of Drug Sensitivity in Cancer (GDSC) databases. Various web platforms and R software, have been utilized. Multiplex immunofluorescence was performed on a human HCC tissue microarray. Results: High ZBED4 expression correlates with poor prognosis and immune cell infiltration in multiple cancers. ZBED4 is potentially involved in the regulation of the tumor environment by T cells, with a focus on CD8'T cells. In HCC, tissues with elevated ZBED4 expression exhibit a higher prevalence of Tregs and neutrophils, whereas those with reduced ZBED4 expression show an increased abundance of CD8' T cells, activated CD4' T cells, gamma/delta T cells, and activated natural killer (NK) cells. Elevated ZBED4 expression in HCC patients is associated with a reduced response to immune checkpoint blockade but an improved response to chemotherapy and most targeted therapies. A multi-gene prognostic signature has been developed and confirmed across various HCC cohorts. Multiplex immunofluorescence study demonstrated that ZBED4 was linked to poor prognosis and negatively correlated with CD8' T cell infiltration. Conclusion: Our research elucidates the role of ZBED4, its strong link to immune infiltration, and its potential as a prognostic and therapeutic biomarker for HCC.