OBJECTIVES: Compare market access (MA) considerations for designated orphan drugs (DOD) in selected countries: EU5, Australia, Canada, Netherlands, Sweden, and US (United States). METHODS: Targeted literature review in MEDLINE, grey literature and health authorities’ websites, establishing DOD-specific pricing and reimbursement policies. RESULTS: DOD-specific policies vary greatly from country to country; regulations target either health technology assessment (HTA) process or pricing rules. In the UK, a specific framework exists for ultra-orphan drugs, applied in the highly specialised technical committee in England, and in Scotland for all ultra-orphan conditions with a substantial medical impact. In Germany, marketing authorisation is considered proof of additional benefit if revenues remain below a €50 million/year threshold; otherwise DODs are assessed as conventional drugs. Conversely, some countries have no DOD-specific HTA processes or pricing regulations, but particular considerations are often employed. Higher cost-effectiveness thresholds in Sweden and the UK are utilized, while in France, both increased flexibility regarding the strength of evidence and exemption from economic evaluation for low budget impact products are engaged. In Australia, the Life Saving Drugs Program provides subsidised access. Furthermore, many countries have special DOD funds to support reimbursement, whilst manufacturers may provide free-access programs via patient groups. Additionally, ranges of managed entry agreements (e.g. pay-for-performance in Italy, price-volume agreement in France, discounts through patient access schemes in the UK) are used to address uncertainties regarding clinical value and high cost of DODs. CONCLUSIONS: Initiatives to enhance MA for DOD remain ambiguous between countries; where some countries have clearly dedicated DOD pricing and reimbursement frameworks, other countries’ processes are less transparent or inexistent. Future work with relevant stakeholders is expected to establish a consistent MA approach to improve patient access.