There is a continuing need for innovative alternative therapies for liver cancer. DNA vaccines for hormone/growth factor immune deprivation represent a feasible and attractive approach for cancer treatment. We reporteda preventive effect of a DNA vaccine based on six copies of the B cell epitope GRP18-27 with optimized adjuvantsagainst H22 hepatocarcinoma. Vaccination with pCR3.1-VS-HSP65-TP-GRP6-M2 (vaccine) elicited much higherlevel of anti-GRP antibodies and proved efficacious in preventing growth of transplanted hepatocarcinomacells. The tumor size and weight were significantly lower (p<0.05) in the vaccine subgroup than in the controlpCR3.1-VS-TP-HSP65-TP-GRP6, pCR3.1-VS-TP-HSP65-TP-M2 or saline subgroups. In addition, significantreduction of tumor-induced angiogenesis associated with intradermal tumors of H22 cells was observed. Thesepotent effects may open ways towards the development of new immunotherapeutic approaches in the treatmentof liver cancer.