OBJECTIVES: Pharmaceutical manufacturers can apply to the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for orphan drug status for pharmaceuticals that treat rare medical conditions. This study compares the policies and processes that influence orphan drug designation in the US and the EU and examines the approval data to explain any differences and/or trends in decision making. METHODS: We conducted a quantitative analysis on the publicly available data on orphan drug approvals released by the FDA and EMA. By looking at the numbers of drugs approved each year, the drugs submitted and approved for orphan indications, and their relevant disease areas we were able to identify any trends and dissimilarities in the organizations final approval decisions. Following this, we performed qualitative research with a focused literature search of the Medline database and relevant websites, to explore the differences in policies and processes between the organizations that may have led to conflicting decisions. RESULTS: There were significant differences in the processes, policies and requirements for orphan drugs. The FDA consistently approved more orphan drugs each year during 2002-2014 (when comparison data were available). However, the numbers of products accepted are converging (e.g. in 2005, the EMA approved approximately 81% fewer orphan drugs; by 2013, this gap was 36%). Some differences in decisions were identified, largely due to different evidence requirements. CONCLUSIONS: The likelihood of a drug gaining orphan drug status in either the US or the EU is dependent on a number of different factors. If the trends persist, it is likely that the organizations will designate a similar number of products as orphan drugs each year, although the approved products may differ. These may affect which organization manufacturers choose to submit applications to first.