Prevention of chronic hepatitis B virus (HBV) infection can successfully reduce the incidence of liver cancer. It is the first example of cancer-preventive vaccine in human, which proves that prevention of the infection of an infectious agent can prevent its related cancer.Chronic HBV infection can lead to chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). HCC is one of the five major cancers in the world population. Hepatitis B virus (HBV) is the most important etiologic agent of liver cancer globally, particularly in high-prevalence areas of liver cancer.The world's first universal HBV vaccination program was launched in Taiwan in July 1984. It has provided evidences that the prevalence of HBV infection has been reduced remarkably to approximately one-tenth of the original prevalence. Furthermore, reduction of the HCC incidence in children aged 6-14 years have been demonstrated in the vaccinated birth cohorts. Recently, we have further provided evidence that the prevention of HCC by this HBV vaccine extends from childhood to early adulthood.The risk of developing HCC for vaccinated cohorts was associated with incomplete HBV vaccination; prenatal maternal hepatitis B surface antigen (HBsAg) seropositivity; and prenatal maternal HBeAg seropositivity. Failure to prevent HCC results mostly from unsuccessful control of HBV infection by highly infectious mothers. Future strategies to increase the global coverage rate of HBV immunization and to interrupt mother-to- infant transmission may enhance the cancer prevention effect of HBV immunization.