OBJECTIVES: Specific regulation and incentives to develop new orphan drugs in US and Europe, as well as increased revenues associated with sales of orphan drugs have boosted the interest of pharmaceutical companies in this field. Pricing is a key success factor for manufacturers as sales volumes are very limited. We investigated the determinants of orphan product prices in five European countries: France, Italy, Germany, Spain and UK, using regression analysis. METHODS: Products with orphan designation approved by EMEA were identified up to June 2009. Yearly prices per product were derived from public prices, WHO defined daily dose, and treatment duration based on guidelines or summary product characteristics. The analysis included disease-related variables: prevalence, disease area, prognosis, age and vulnerability of target population, seriousness, number of available treatments and course of illness, and drug-related parameters: year of approval, trial size, number of trials, comparator in trial, ATC code, evidence of benefit. A generalized linear model was used to identify price predictors for the 5 countries. RESULTS: Fifty-one products were identified of which respectively 37, 35, 28, 36 and 39 were available in France, Germany, Italy, Spain and UK respectively. Available products did not overlap across countries. Prices were highest in Italy and lowest in UK. No significant correlation was found between any of the variables and price. Low prevalence and low number of available treatment alternatives seemed associated with high prices, but these trends were not statistically significant. CONCLUSIONS: Pricing of orphan drugs is a complex process, with no identifiable objective price determinant. Patient group pressure, low overall impact on health care expenditure budget, influence of opinion leaders and the ability of leveraging the importance of unmet need in the target population might play an important role. This analysis generated hypotheses for further research into drivers of prices for orphan drugs.