Abstract Liver cancer is one of the five leading cancer death in human. Chronic hepatitis B virus (HBV) infection is the most common cause of liver cancer in the world. In high incidence regions for liver cancer, such as Asia and Africa, HBV infection is highly endemic. Primary prevention by universal HBV immunization in infancy is currently the most effective way to prevent liver cancer. Using antiviral therapy to treat hepatitis B or hepatitis C with active viral replication is the method of secondary liver cancer prevention. Screening is needed to pick up high risk subjects of liver cancer (e.g. screening HBsAg among males > 40 years old in endemic areas of HBV infection and children of HBsAg carrier mothers, intravenous drug users; and screening hepatitis C virus antibody (anti-HCV) among intravenous drug users, children of HCV infected mothers, etc.). Regular follow-up of those subjects with positive serum HBsAg /anti-HCV is very helpful to find out the suitable target subjects for secondary prevention. We have provided the first evidence to support that universal HBV immunization can effectively reduce approximately 90% of chronic HBV infection and 70% of the incidence of hepatocellular carcinoma in children and adolescents. After universal HBV immunization in Taiwan, around 90% of chronic HBV infection occurs in children of mothers with chronic HBV infection. Globally, the difficulties of liver cancer prevention include inadequate resources, poor compliance, and breakthrough infection of HBV by mother-to-infant transmission. In order to prevent mother-to-infant transmission, globally there are three main HBV immunization strategies to screen or not to screen the HBsAg /HBeAg among pregnant women, and to give or not to give HBIG. In under-developed or developing environment with limited resources, no screening of maternal HBsAg/HBeAg and thus no HBIG but three doses of HBV vaccine are given to the infants. This is the most commonly applied strategy in the world. Another two different screening strategies for pregnant women were provided in the environment with relatively adequate resources: (1) screening pregnant women for HBsAg only (e.g. in the U.S.A) and give HBIG for all infants of HBsAg positive mothers, or (2) screening for both HBsAg and HBeAg (e.g. in Taiwan), and give HBIG for infants of HBeAg positive HBsAg carrier mothers only. Which of the above mentioned strategies are more cost-effective is still debatable Our recent studies revealed that infants born to HBeAg seropositive HBsAg carrier mothers were the major high risk group of breakthrough chronic HBV infection in an HBV immunized birth cohort. Pregnant women screening for both HBsAg and HBeAg is favorable for both maternal- child health and liver cancer prevention. In conclusion, universal HBV immunization and screening of high risk groups are needed for a successful control of liver cancer. The successful experience of liver cancer prevention may be applied to the prevention of other infection related cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY26-03. doi:1538-7445.AM2012-SY26-03