OBJECTIVES: Since the enactment of the Orphan Drug Act of 1983, companies have increasingly focused their research pipeline on orphan drugs, including ultra-orphan drugs for rare diseases and conditions with a very low prevalence. This study describe trends in the approval of ultra-orphan drugs by the FDA in the period 1983-2014. METHODS: Regulatory data derived from the FDA, and prevalence data derived from the FDA and the EMA and other publicly available sources. Descriptive statistics were performed to describe orphan approvals by disease prevalence. Chi-square test was performed to assess differences in proportions. The statistical significant level was set a priori at p ≤ 0.05. RESULTS: In the period 1983-1989, the FDA approved an average ± standard deviation of 6.6 ± 3.1 orphan drugs per year; 15.6± 2.7 in the 1990s, 15.0± 2.4 in the 2000s, and 27.4±10.5 in the period January 2010-December 2014. Prevalence information was available for 60.5% of the 489 orphan drug approved by the FDA. Drugs approved for use in diseases with a prevalence of less than 1000 patients represented 6.8% of all orphan drugs approved in the US during the study period with prevalence information. Drugs approved for diseases with a prevalence of less than 1000 patients represented 6.3%, 3.3%, 5.8%, and 11.6% of all orphan drugs approved in the US in the periods 1983-1989, 1990s, 2000s, and 2010-2014, respectively. Drugs approved for diseases with a prevalence of less than 5000 patients represented 8.4%, 12.9%, 19.1%, and 24.0% of all orphan drugs approved in the US in the periods 1983-1989, 1990s, 2000s, and 2010- 2014, respectively. CONCLUSIONS: The number and percentage of ultra-orphan drugs approved by the FDA increased in comparison with orphan drugs for rare diseases with a larger number of patients in the period 1983-2014.