OBJECTIVES: In 2011, the introduction of boceprevir and telaprevir was hailed as a breakthrough in the hepatitis C (HCV) treatment paradigm, but these treatments were not widely adopted due to cost and safety concerns. 4 years on, the introduction of newer, more effective therapies (e.g. simeprevir and sofosbuvir) has re-revolutionized the HCV space. However, cost concerns continue to limit the number of patients being treated with new medicines. To inform future submissions, HCV reimbursement decisions across 5 HTA agencies were assessed and the underlying rationale examined. METHODS: NICE, SMC, PBAC, CADTH, and TLV were searched for guidance on HCV medicines between December 2010 and December 2014. Recommendations for and rationale behind each decision were extracted. RESULTS: Boceprevir and telaprevir had each been assessed 6 times across the different agencies including resubmissions: PBAC initially rejected both, then restricted both dependent on reduced price at resubmission; CADTH also restricted both dependent on reduced price. Submissions were accepted in-line with the label by the other agencies. Reasons for rejection/restriction of boceprevir and telaprevir included cost-effectiveness concerns, uncertain efficacy in some patient populations, and safety concerns. Simeprevir had been assessed 4 times with 1 in development: CADTH and TLV restricted simeprevir due to uncertainty over cost-effectiveness and efficacy in some genotypes; PBAC and SMC accepted simeprevir. Sofosbuvir had been assessed 4 times with 1 in development: PBAC rejected sofosbuvir due to unacceptable cost-effectiveness and high budget impact; CADTH and TLV restricted sofosbuvir dependent on reduced price; SMC accepted sofosbuvir. CONCLUSIONS: Despite higher cure rates achieved with newer treatment options, cost-effectiveness concerns remain the primary reason for rejection or restriction of HCV therapies by HTA agencies. Manufacturers should not assume that high clinical efficacy will equate to reimbursement and treatment uptake, as therapies must also convincingly demonstrate cost-effectiveness as well as justifying budget impact.