OBJECTIVES: Ultra-orphan diseases affect a very small patient population, defined by the National Institute for Health and Care Excellence (NICE) as those diseases with a prevalence of ≤ 1:50,000. Medicines for these indications are difficult to develop in part due to challenges associated with recruiting for clinical trials from a small patient population. Within this context, global payer bodies have assessed these therapies with modified evidence requirements and opportunity for very high prices. We performed a health technology assessment (HTA) review of two ultra-orphan products – eculizumab/Soliris and iduronate-2-sulfatase (IDS)/Elaprase – to gain insight into the evolving HTA evidence requirements for ultra-orphan medicines and comparatively evaluate key decision drivers across geographies. METHODS: We scanned global HTAs published before end of May 2014 to identify the two most widely assessed ultra-orphan therapies that have variable reimbursement decision outcomes (eculizumab/Soliris and IDS/Elaprase). To evaluate pivotal decision drivers, we analyzed HTAs across several criteria, including clinical efficacy, unmet need, strength of evidence, cost-effectiveness and burden of illness. RESULTS: We identified HTAs in seven countries. For both products, reimbursement decisions varied across agencies. Key decision drivers included cost-effectiveness, clinical efficacy, risk-sharing schemes, and lowered evidence requirements/ special criteria for ultra-orphan medicines. Assessments rejecting Soliris and Elaprase (e.g., Australia, Canada, UK) did so based on cost-effectiveness and lack of long-term survival data. Notably, the NICE Highly Specialized Technology Committee requested unprecedented justification of Soliris pricing. Some agencies (e.g, Scottish Medicines Consortium [SMC]) preemptively rejected the products due to manufacturer non-submission of required data. In Australia, Soliris gained recommendation alongside a risk-sharing scheme while Elaprase gained recommendation under Life Saving Drugs Program criteria. CONCLUSIONS: Eculizumab and IDS are among a select list of therapies commanding very high prices globally. This study demonstrates variability in decision criteria and approaches across HTA agencies for such high-priced ultra-orphan products.