The therapeutic landscape of Hepatitis C virus (HCV) infection has changed dramatically since 2013 when “life-saving” direct-acting antivirals (HCV-DAAs) entered the global market. Although behind such a huge biomedical stride, their high prices have been criticised globally as a barrier to patient access and a threat to health care financing. In order to understand the emerging challenges of high-cost medicines, this study conducted a comparative multinational analysis of pricing and reimbursement decision-making processes for HCV-DAAs in Japan, the U.S. and England. Overall, the list prices of HCV-DAAs differed largely by country (the U.S.>England>Japan) and by pharmaceutical company. With respect to reimbursement decisions, the common obstacle was the prediction of and the management of demand. Access to HCV-DAAs was least controlled in Japan and most strictly controlled in the U.S. where certain individuals (those with HIV co-infection, a history of illicit drug and alcohol use) were systematically excluded. In England, access, in theory, was controlled by the disease stage, but in practice, implementation was largely delayed and the number of patients to be treated annually has been strictly managed. The study found that despite the common obstacle of budget impact, the countries were faced with different challenges. In Japan, there has been a growing recognition of the importance of cost considerations. While this may be a positive development, the implementation of health technology assessment (HTA) must reflect the existing health system, policies and culture. In the U.S., increased focus should be placed on its systematic problems such as its fragmented health system. The challenge for England was more specific, namely, the disparity between the current budget and the cost-effectiveness threshold must be reconsidered, given the ability of the NHS to produce health benefits from existing activities.