Background & Aims The incidence of hepatocellular carcinoma (HCC) increases with age, but protective antibody responses decrease with time after infants are immunized against hepatitis B virus (HBV). We investigated whether immunization of infants against HBV prevents their developing HCC as adults. We also searched for strategies to maximize the cancer-preventive effects. Methods We collected data from 2 Taiwan HCC registry systems on 1509 patients (6–26 years old) diagnosed with HCC from 1983 through 2011. Data on history of HBV immunization and prenatal maternal levels of HBV antigens of all HCC patients born after July 1984 were retrieved from the HBV immunization data bank of the Taiwan Center for Disease Control. We collected data on birth cohort-specific populations (6–26 years old) of Taiwan using the National Household Registry System. Rates of HCC incidence per 105 person-years were derived by dividing the number of patients with HCC by the person-years of the general population. Relative risks (RR) for HCC were estimated by Poisson regression analysis in vaccinated vs unvaccinated birth cohorts. We stratified patients by age group to evaluate the association of birth cohorts and HCC risks. Results Of the 1509 patients with HCC, 1343 were born before, and 166 were born after, the HBV vaccination program began. HCC incidence per 105 person-years was 0.92 in the unvaccinated cohort and 0.23 in the vaccinated birth cohorts. The RRs for HCC in patients 6–9 years old, 10–14 years old, 15–19 years old, and 20–26 years old who were vaccinated vs unvaccinated were 0.26 (95% confidence interval [CI], 0.17–0.40), 0.34 (95% CI, 0.25–0.48), 0.37 (95% CI, 0.25–0.51), and 0.42 (95% CI, 0.32–0.56), respectively. The RR for HCC in 6- to 26-year-olds was lower in the later vs the earlier cohorts (born in 1992–2005 vs 1986–1992; P <.001 and 1986–1992 vs 1984–1986; P < .002). Transmission of HBV from highly infectious mothers and incomplete immunization were associated with development of HCC. Conclusions Based on an analysis of 1509 patients with HCC in Taiwan, immunization of infants against HBV reduces their risk of developing HCC as children and young adults. Improving HBV vaccination strategies and overcoming risk factors could reduce the incidence of liver cancer.