Hepatitis B virus (HBV) infection is an important public health problem all over the world. Vaccination is one way to prevent it, and several strategies can be used depending on endemicity, the main pattern of HBV transmission and the demographic structure of the population. In this study, an economic comparison of 3 vaccination strategies (mass adolescent vaccination, mass infant vaccination and mass combined vaccination) was performed in Catalonia, Spain. Screening pregnant women for HBV infection in combination with these strategies was also evaluated. Epidemiological models to analyse patterns of HBV infection with and without vaccination and to calculate HBV-associated costs were designed. Comparison between strategies was done using cost-effectiveness analysis from the perspective of the healthcare system. Epidemiological model results indicate that implementation of HBV vaccination could prevent as many as 104,778 new acute infections, and avoid up to 5239 chronic infections, 2096 cases of cirrhosis and 419 cases of hepatocarcinoma over a 20-year period in Catalonia. Cost-effectiveness analysis shows that mass adolescent vaccination is the most efficient strategy, with lower costs per avoided case than the other 2 strategies. When any of these strategies is complemented by screening for HBV in pregnant women, the number of avoided cases is always higher and the cost per avoided case decreases or remains unchanged.