OBJECTIVES: To characterize pricing for Orphan drugs in the US and analyze pricing variation across year of launch, extent of competition, and disease morbidity/mortality. METHODS: US FDA Drug Approval and Orphan Drug Databases were downloaded for the period 2015 to 2020, along with dosing and administration data from Prescriber Information labels. Unit WAC cost was obtained from Analysource Pricing Data^TM. Annual per patient therapy costs for first year were computed to standardize across the various indications. Drug dosing and administration variations were normalized to account for dosing cycles and periodicity of treatment. Average adult dosing of 70 kg body mass and 1.7 m² body surface area was assumed. In order to minimize price variation across presentations, the least cost units were utilized to minimize wastage. RESULTS: Since 2015, 292 novel drugs have received FDA approval. Of these, 89 were granted the Orphan designation for adults with available WAC. Nearly half of these are approved for oncology indications (n=40). The highest number of drugs approved in a year was in 2018, (n=23) and lowest was in 2016 (n=7). Annual costs range from $3,600 for Tuberculosis to $2.99M for ADA-SCID. Median per patient cost by Year of Launch was 2015 = $167K; 2016 = $187K; 2017 = $186K; 2018 = $312K; 2019 = $178K; 2020 = $266K. 55 indications (82%) had only one approval over this period. Multiple Myeloma had the most approvals (n=7) with annual costs ranging from $71.5K to $281K. Median oncology rare disease costs are $200K versus non oncology rare diseases $242K. CONCLUSIONS: In this six-year review of Orphan drug pricing demonstrate increasing annual therapy costs per patient. Majority of the diseases have only 1 approved therapy, hereby limiting competitive pricing dynamics. Innovations that impact significant mortality/morbidity command higher annual costs.