OBJECTIVES: To analyze trends and explanatory factors associated with the average wholesale price (AWP) at market entry for orphan drugs for chronic use approved by the FDA in the period 1983-2014. METHODS: Regulatory information was obtained from the FDA website. Drugs were classified using the WHO Anatomical Therapeutic Chemical (ATC) Classification System. Daily doses (DDD) were collected from the FDA-approved labels. AWPs were collected from the Redbook (Truven Health Analytics). Prices were adjusted to 2014 dollars using the consumer price index. Descriptive statistics, compound annual growth rates (CAGR) and multiple linear regression analyses were conducted using Stata 14. RESULTS: The FDA approved 203 orphan drugs for chronic use (41.7% of 487 FDA-approved orphan drugs) in the study period. Most orphan drugs for chronic use were new drug applications (NDAs) (n=166; 81.8% of the approvals), approved using the priority review process (107; 52.7%), and oral formulations (112; 55.2%). By December 31, 2014, 21.7% (n=44) of the drugs had generic competition and 11.8% (n=24) were discontinued from the market. The inflation-adjusted median cost per year at market entry increased from $1,573 in 1983-1984 to $100,555 in 2010-2014, representing an increase of 63.9 times the inflation-adjusted median cost during the study period. Biologic License Application (BLAs) approval (p< 0.0030), non-oral route formulation (p<0.0000), FDA priority review (p<0.0000), and year of approval (p<0.0000) were significantly associated with orphan drug prices at market entry. CONCLUSIONS: An increasing number of orphan drugs have been approved by the FDA since the enactment of the Orphan Drug Act in 1983. Median prices at market entry of orphan drugs for chronic use have doubled every five years. FDA application type, review process, approval year, and route of administration were the main factors associated with the price at market entry of orphan drugs for chronic use