Immunization with effective cancer vaccines can offer a much needed adjuvant therapy to fill the treatment gap after liver resection to prevent relapse of hepatocellular carcinoma (HCC). However, current HCC cancer vaccines are mostly based on native shared‐self/tumor antigens that are only able to induce weak immune responses. In this study we investigated whether the HCC‐associated self/tumor antigen of alpha‐fetoprotein (AFP) could be engineered to create an effective vaccine to break immune tolerance and potently activate CD8 T cells to prevent clinically relevant carcinogen‐induced autochthonous HCC in mice. We found that the approach of computer‐guided methodical epitope‐optimization created a highly immunogenic AFP and that immunization with lentivector expressing the epitope‐optimized AFP, but not wild‐type AFP, potently activated CD8 T cells. Critically, the activated CD8 T cells not only cross‐recognized short synthetic wild‐type AFP peptides, but also recognized and killed tumor cells expressing wild‐type AFP protein. Immunization with lentivector expressing optimized AFP, but not native AFP, completely protected mice from tumor challenge and reduced the incidence of carcinogen‐induced autochthonous HCC. In addition, prime‐boost immunization with the optimized AFP significantly increased the frequency of AFP‐specific memory CD8 T cells in the liver that were highly effective against emerging HCC tumor cells, further enhancing the tumor prevention of carcinogen‐induced autochthonous HCC. Conclusions: Epitope‐optimization is required to break immune tolerance and potently activate AFP‐specific CD8 T cells, generating effective antitumor effect to prevent clinically relevant carcinogen‐induced autochthonous HCC in mice. Our study provides a practical roadmap to develop effective human HCC vaccines that may result in an improved outcome compared to the current HCC vaccines based on wild‐type AFP. (Hepatology 2014;59:1448‐1458)