OBJECTIVES:  We explore the criteria informing coverage decisions of orphan drugs across different diagnostic conditions to understand if different HTA processes result in preferential assessments, conflicting recommendations, and inequitable access to innovative treatment for rare diseases. METHODS: Countries included were England, France, Germany, Italy, Poland, Scotland, Spain, and Sweden. Through a selection of orphan drug appraisals between 2006 and 2012, twenty orphan (including ultra-orphan) drug-indication pairs were identified and selected. The sample was split equally between oncology and non-oncology indications. Submitted clinical and economic evidence was identified, collected and analysed systematically and on a case-by-case basis, and following a validated methodological framework. Coverage and funding options based on HTA recommendations as well as on criteria or policies other than HTA were also considered. RESULTS:  There is huge heterogeneity in coverage recommendations depending on setting. In general, there seems to be a higher willingness to pay for orphan drugs, either through a higher ICER threshold, or only when costs are not exceeding the budget. Additional criteria related to the rarity of diseases or special considerations, particularly centered on unmet need and severity, seem to play an important and increasing role beyond strict cost-effectiveness criteria. Decisions about purchasing may be influenced by factors beyond HTA (e.g. early access schemes), which may be relevant to orphan drugs. Little uniformity exists in the time taken to assess a drug following marketing authorisation, leading to inequities in access. CONCLUSIONS:  Despite the extensive and ever increasing use of HTA for orphan drugs, the variations in HTA recommendation outcomes across jurisdictions and the –often- very significant time lapses between the date of marketing authorisation, the final HTA recommendation and the eventual funding decision, imply variations in access and highlight the importance of establishing specific policies for orphan drugs to ensure fair assessment and equitable access to treatment for rare diseases.