Before 1970, approximately 6% of multi-transfused recipients acquired a transfusion-transmitted Hepatitis B virus (HBV) infection. The safety improvements since then have been tremendous. From a level of a few infections per 1000 donations, the risk today, depending on the screening algorithm and additional measurements performed, has decreased to around 1:500,000 to 1:1,000,000, an improvement greater than 1000-fold compared to 50 years ago. This enormous gain in safety has been achieved through many factors, including development of increasingly more sensitive Hepatitis B antigen (HBsAg) assays; the adoption in some countries of hepatitis B core antibody (anti-HBc) screening; an improved donor selection procedure; HBV vaccination programs; and finally the introduction of HBV nucleic acid testing (NAT). Because there is a tendency in transfusion medicine to add one safety measure on top of another to approach the ultimate goal of zero risks, costs become increasingly a matter of debate. It is obvious that any new measure in addition to existing methods or measures will have very poor cost effectiveness. Therefore each country needs to perform its own calculation based on the country's own epidemiology, resources, political and public awareness of the risks, in order to choose the correct and most cost-efficient measures. Ideally, each country would make decisions regarding implementation of additional blood safety measures in the context of both the perceived benefit and the allocation of overall health care resources.