OBJECTIVES: Our objective is to identify key characteristics and trends in ultra-orphan drugs’ (UODs) market access and pricing. METHODS: Our analysis was based on 25 UODs currently available in France. We reviewed data collected from EMA, HAS (French HTA), FDA, Orphanet®, Eurordis®, clinicaltrial.gov websites, promotors press releases, financial report, IHS® and Micromedex® databases. For each UOD, an analysis of their indication, French HTA agency assessments and US & major EU country cost of treatment was performed. RESULTS: Among these 25 drugs, 17 drugs had only one indication and 4 indications have multiple marketed drugs. 5 companies holds 68% of the UOD global market. Access was achieved earlier in the US for 68% of drugs and 80% of products were granted an Orphan Drug Designation. Most UODs had limited development programs, enrolling 59 patients per trial on average, commonly adopting intermediate endpoints, and using single arm trials.  In France, HAS has given the highest available SMR level for all these UODs, leading to full reimbursement. The majority (65%) of indications have the highest ASMR levels (I, II or III), allowing European price eligibility. The yearly average treatment cost per patient was higher in the US for 54% of these products, equivalent for 33%, and lower for 13%. Average cost was 442k€ in the US vs 376k€ in Europe. In France, treatment cost was inversely correlated with population size, but not to the ASMR level. Per patient annual treatment costs tend to increase over time in Europe. CONCLUSIONS: Despite the small patient population, the UODs market shows a considerable development activity. However limited development programs and evidence uncertainty is a major consideration regarding the UODs, they have been able to achieve good HTA scores, favorable reimbursement decisions and very high prices.