The duration of protection provided by hepatitis B vaccine is still unknown but can be estimated through long-term follow-up studies. Electronic databases and conference databases to December 2008 were searched. Reference lists of articles were screened and the studies authors and manufacturers were contacted for additional unpublished references. Randomized clinical trials and prospective cohort studies addressing the long-term protective effect of hepatitis B vaccine were included in this meta-analysis. We assessed 42 separate cohorts involving overall 11,090 subjects; 34 cohorts involving 9356 subjects were included in the final meta-analysis. Results indicate that the overall cumulative incidence of HBV breakthrough infection 5-20 years post-primary vaccination was 0.007 [95% CI: 0.005 to 0.010] with a variation among studies from 0 to 0.094. Available data do not allow us to exclude an increased risk for infection with time since vaccination. We conclude that the protection provided by three or four doses of monovalent HB vaccine persists for at least two decades in the great majority of immunocompetent individuals. Additional studies are needed for assessing vaccine efficacy for longer periods of time and the need of booster doses in different subgroups of population.