Alaska Native people experience the highest rates of acute and chronic hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC) in the United States. We examined the effect of a universal newborn immunization with hepatitis B vaccine and mass population screening immunization program initiated in 1984 on rates of HBV and HCC in children 25 years later. During this time, the population of Alaska Native people grew from an estimated 75,000 to 130,000 persons. A surveillance system to detect acute HBV infection in Alaska Native facilities was established in 1981. Cases of HCC in children under 20 years of age were identified using a National Cancer Institute (NCI)-funded Cancer Registry established in 1969 coupled with an active surveillance program of screening persons with chronic HBV semiannually for alpha-fetoprotein since 1982. The incidence of acute symptomatic HBV infection in persons <20 years of age fell from cases 19/100,000 in 1981-1982 to 0/100,000 in 1993-1994. No cases of acute HBV have occurred in children since 1992. The incidence of HCC in persons <20 years decreased from 3/100,000 in 1984-1988 to zero in 1995-1999 and no cases have occurred since 1999. The number of identified hepatitis B surface antigen-positive children <20 years in the Alaska Native population declined from 657 in 1987 to two in 2008. Conclusion: Universal newborn vaccination coupled with mass screening and immunization of susceptible Alaska Natives has eliminated HCC and acute symptomatic HBV infection among Alaska Native children and this approach is the best way to prevent HBV-related disease in children. (HEPATOLOGY 2011;)