The majority of hepatocellular carcinoma (HCC) patients have a poor prognosis with current therapies, andnew approaches are urgently needed. We have developed a novel therapeutic cancer vaccine platform based ontumor cell derived autophagosomes (DRibbles) for cancer immunotherapy. We here evaluated the effectivenessof DRibbles-pulsed dendritic cell (DC) immunization to induce anti-tumor immunity in BALB/c mouse HCCand humanized HCC mouse models generated by transplantation of human HCC cells (HepG2) into BALB/c-numice. DRibbles were enriched from H22 or BNL cells, BALB/c-derived HCC cell lines, by inducing autophagyand blocking protein degradation. DRibbles-pulsed DC immunization induced a specific T cell response againstHCC and resulted in significant inhibition of tumor growth compared to mice treated with DCs alone. Antitumorefficacy of the DCs-DRibbles vaccine was also demonstrated in a humanized HCC mouse model. Theresults indicated that HCC/DRibbles-pulsed DCs immunotherapy might be useful for suppressing the growthof residual tumors after primary therapy of human HCC.