OBJECTIVES: The United States (US) and the European Union (EU) implemented regulations for encouraging the development of drugs for rare diseases. Criteria for Orphan designation is generally based on the number of patients affected by the disease (<200,000 US patients and <5 in 10,000 EU patients). The EU also requires that a satisfactory alternative treatment is not available or that the new drug is significantly better than drugs currently marketed. We examined the characteristics of orphan drug (OD) designations and approvals by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) between 2000 and 2011. METHODS: Data for orphan designations and approvals were extracted from the FDA and EMA online databases for the period 2000-2011. Data were updated to September 14, 2012. The time for OD designation to approval was estimated. Descriptive analysis, chi-square test, and group comparison t-tests were used in the analysis. RESULTS: The FDA granted 1558 orphan designations for 1133 different products, and 149 approvals (9.6% of designated products), and the EMA 935 designations for 639 different products and 88 (9.4%) approvals during the study period. The time from OD designation to approval was 2.74±2.39 years in the FDA and 3.31±1.99 years in EME (p<0.05). EMA approved a larger number of designations (15.2%) than the FDA (12.3%) for the 569 products designated by both agencies; 67% of these products were first designated by the FDA and 78% of the 50 products approved by both agencies were approved first by EMA (p<0.001). CONCLUSIONS: The EU had more restrictive criteria for orphan designation and significantly longer approval times, less orphan designations, and fewer product approvals than the US. Harmonization of the Orphan drug regulatory processes of FDA and EME could result in improved access to ODs in the US and the EU.