OBJECTIVES: We assessed the prevalence of shortages of drugs approved for orphan indications and evaluated the characteristics of the orphan drugs reported in short supply in the US. METHODS: Orphan approval data were collected from the US FDA webpage. Shortage data were provided by the Drug Information Service, University of Utah Hospitals and Clinics (UU). The prevalence of shortages was estimated as a percentage of the total number of orphan indications approved in the US as of September 25, 2013. RESULTS: The FDA approved 449 orphan indications for 338 products (66.0% molecular entities, 23.7% therapeutic biologics, and 10.4% other biologics). Injectable products represented 59.7%, oral products 30.7% and other 9.6% of the orphan indications. The average number of orphan indications per year increased from 6.9 in 1983-1989 to 23.3 in 2010-2013. The UU listed 1,740 shortages in the period 2000-09/25/2013. A total of 146 (8.4%) of shortages were for products with orphan indications. Shortages were estimated to affect 28.5% of FDA approved orphan indications (128 shortages out of 449 orphan indications approved by the FDA), this included 36.0% of indications for molecular entities, 15.8% of for therapeutic biologics, and 6.7% for biologics. The average estimated duration of shortages was 252.1±322.1 days for drugs with orphan indications and 270.3±336.3 days for other drugs (differences not statistically significant).. The reason for the shortage was unknown for 50.2% of the shortages. Drugs with orphan indications were significantly more likely to have manufacturing problems as the reason for the shortage (67.6%) than other drugs (52.9%, p=0.02).. CONCLUSIONS: Over one-fourth of the drugs with approved orphan indications were reported in short supply in the US. Problems with manufacturing represented most of the reported causes of shortages. Additional research is needed to assess the risk factors, causes and clinical impact of orphan drug shortages..