OBJECTIVES: The study was conducted aiming to compare the listing process and factors which have affected the listing decisions made by NICE, PBAC, CADTH, and Taiwan PBRS (Pharmaceutical Benefit and Reimbursement Scheme) Joint Committee as well as to analyze the expenditure trend of orphan drug over time in Taiwan. METHODS: Eculizumab was chosen as the case to be analyzed in the study, and the documents related to rules of reimbursement in orphan drug status and the recommendations given by NICE, PBAC, CADTH and Taiwan NHIA were retrieved. The factors influencing whether eculizumab was reimbursed were identified and further processed. In addition, the representatives of Taiwan Foundation for Rare Disorders (TFRD) and the decision makers of PBRS Committee were interviewed to gather advice on improving the reimbursement procedures. For the cost evaluations, data from the public databases of NHIA and TFRD were analyzed. RESULTS: The total cost of orphan drug had increased from 0.51 to 3.63 billion NTD over 2005-2014. The orphan drug expenditure percentage of NHI’s total drug expenditure has risen from 0.46 in 2005 to 2.26 in 2014. Four key factors which have higher impacts on the listing decisions of eculizumab among Taiwan, UK, Australia and Canada were identified: clinical evidence, drug license management, reimbursement processes and type of funding source. Moreover, developing a system to monitor and manage the licensing process and setting up special programs similar to the Life-saving drugs program(LSDP) in Australia to serve patients with urgent medical needs were suggested by the representatives of TFRD and PBRS Joint Committee. CONCLUSIONS: The growing expenditure of orphan drug has increased the burden of Taiwan NHI. A validated and efficient licensing process must be established for the sake of ensuring clinical safety of orphan drugs. Furthermore, in order to fulfill unmet medical needs, new program implementation was also suggested to expedite the process of orphan drug approval and reimbursement.