Primary hepatocellular carcinoma is the commonest cancer in The Gambia. The Gambia Hepatitis Intervention Study (GHIS) was established in 1986 to evaluate the protective effectiveness of infant hepatitis B immunization in the prevention of chronic liver disease, particularly, hepatocellular carcinoma and cirrhosis later in adult life. This program was designed based on a series of assumptions. Here, we used data from observational and epidemiologic studies developed since 1986 to examine the validity of these assumptions. We found that (a) hepatitis B vaccine coverage was 15% more than originally assumed, (b) protection against hepatitis B virus (HBV) infection was not dependent on the number of vaccine doses received, (c) perinatal infection with HBV was of negligible importance, and (d) the HBV attributable risk of hepatocellular carcinoma at age < 50 was 70% to 80%, lower than initially assumed. Based on these data, the final outcome of the GHIS should be measurable from 2017, sooner than originally assumed. The GHIS strategy takes into account-specific patterns of virus epidemiology and natural history of hepatocellular carcinoma in Africa and provides a model for integrating and evaluating new vaccines into the Expanded Programme of Immunization of sub-Saharan African countries.