OBJECTIVES: Ultra orphan therapies are indicated for rare diseases affecting less than a few thousand patients. The annual and lifetime per patient cost of these treatments have generated controversy and policy questions regarding cost effectiveness and reimbursement. The objective of this analysis was to review all available cost effectiveness studies and develop lessons for policy development for ultra orphan therapies. METHODS: Fifteen European Medicines Agency (EMA) and Food and Drug Administration (FDA) approved ultra orphan drugs were identified and reviewed for their published cost effectiveness through studies in peer-reviewed journals and Health Technology Assessments (HTAs). Data was collected for: (1) Product (2) Indication (3) Model design and assumptions (4) Author of the analysis (manufacturer, HTA or academic group) (5) Cost effectiveness results and (5) Sensitivity analysis results. All cost effectiveness ratios were converted to 2013 US dollar amounts using historical currency conversion rates. RESULTS: For fifteen EMA and FDA approved ultra orphan therapies, eight cost effectiveness studies were identified for seven products (50%). Four of these studies were conducted by the sponsor (as part of the HTA submission), two were conducted by HTAs and two were from academic groups. All models were developed for a life time horizon. In the base case scenario, the median base case incremental cost effectiveness ratio (ICER) was $591,200 per quality adjusted life years (QALYs) (range: $391,120 to $7,425,000).  The sensitivity analyses results had a median ICER of $1,958,674 per QALY, with a maximum ICER of $10,395,000. All reported ICERs exceeded the maximum accepted thresholds for end of life care therapies. CONCLUSIONS: Review of cost effectiveness studies for ultra orphan therapies shows that none were able to show ICERs within typical thresholds. These results suggest a need for new policy regarding acceptable threshold, or type of models for assessing the cost effectiveness of ultra orphan therapies.