OBJECTIVES: Budget impact (BI) of orphan drugs (ODs) has increased over the past 10 years as more ODs entered the market since the introduction of the EU Regulation on Orphan Medicinal Products. The aim of this study is to determine the BI of ODs in a selection of countries where a large number of authorized ODs are reimbursed. METHODS: Public data on OD expenditure in Denmark was collected. The BI was calculated per product for the period 2005-2009. Subgroup analyses were performed for different types of treatment setting and ATC classes. The results of Denmark were compared to data collected for France (total OD costs for 2002-2009 specified per treatment setting) and for Belgium (budget estimates per product for 2008). RESULTS: Total BI of ODs in Denmark increased from 20.3M€ for 13 reimbursed ODs out of 22 (59%) authorized ODs in 2005 to €58.3M for 41 out of 60 (68%) authorized ODs in 2009. Highest costs were for oncology drugs (57%-67% of total BI in 2005-2009) and for metabolism drugs (19%-30% in 2005-2009). Outpatient drugs accounted for 0.01% (2005) to 1.55% (2009) of total BI of ODs. In France, 34 ODs were reimbursed in 2008 and the BI increased from €71M in 2002 to €496M in 2008. In 2008, the BI represented 1.8% of the total value of drugs sold. The situation in Belgium is comparable as the total BI of ODs was €66.2M in 2008 representing 2% of total reimbursed drug costs. CONCLUSIONS: Although cost per patient is relatively high, total BI for a country is still modest as a result of lower volumes used. The results show a consistent picture for OD expenditure across different health care systems. Budget restrictions are not widely used for ODs but this might change when the anticipated increase in BI of ODs becomes more apparent.