OBJECTIVES: To compare the reimbursement decisions for orphan drugs across leading HTA agencies. METHODS: Regulatory approvals for orphan drugs were retrieved from the EMA (Europe), FDA (US) and TGA (Australia) websites. The HTA reports published by AHRQ (US), NICE (England and Wales), HAS (France), IQWiG (Germany), PBAC (Australia), and SMC (Scotland) for orphan diseases were assessed and the decisions were classified as positive, negative or deferred. RESULTS: Overall, 86 drugs were approved by EMA for 102 orphan conditions, 194 drugs were approved by FDA for 306 orphan conditions and 139 drugs were approved by TGA for 178 orphan conditions. Highest percentage of HTA reports were published by HAS (84%), followed by SMC (76%), PBAC (48%), IQWiG (32%) and NICE (26%), whereas no HTA reports were published by AHRQ. Overall, an increase in the number of HTAs was noted over the years, with maximum being published in 2014 and 2015. Highest percentage of positive decisions was provided by HAS (95%), followed by PBAC (64%), NICE (62%), SMC (54%) and IQWiG (39%). However, most positive decisions granted by PBAC and SMC included restricted recommendations, with patient sub-groups and distribution arrangements being the common restriction criteria. For the negative decisions, lack of compelling clinical evidence was identified as major driver by IQWiG and HAS, whereas NICE, PBAC and SMC cited high ICER values and economic modelling-related uncertainties as key factors. CONCLUSIONS: Although there is a high unmet need in the orphan disease area, the number of HTAs conducted remains low especially for NICE and IQWiG. However, the increasing trend of assessments indicates the growing focus of HTA bodies in this area. Considering the variability in priorities and evidence requirements for orphan drugs across HTA agencies, a detailed analysis of the key decision drivers will allow manufacturers to address payer concerns and enable optimal access to orphan drugs.