OBJECTIVES: When undergoing a health technology assessment (HTA) in France, drugs are assigned ASMR score which represents the improvement in medical benefit bringing by the new therapy. Orphan drugs (ODs) are frequently granted higher ASMR compared to medicines for common diseases. The study aimed at identifying drivers of ASMR of ODs. METHODS: All ODs approved between 2000 and May 2015 by the European Medicines Agency (EMA) were identified. ASMR and other HTA details were available from HTA reports. The following parameters were studies: prevalence, severity, age of target population, availability of alternative treatment, ATC class, treatment line, type of clinical trial, comparator and primary endpoint, approval date, and HTA date. Association between ASMR and the parameters was studied in the bivariate analysis. A multinomial regression model was also developed. Only first approved indications were considered. RESULTS: From 102 OD approved by the EMA, 91 has undergone HTA in France and 88 were included in the analysis (one molecule was rejected and for two others ASMR score was not assessed). In the bivariate analysis ASMR were significantly associated with ATC class and disease prevalence. After the adjustment for other covariates, significant association remained only for ATC class (p=0.02). Other parameters having a statistically significant impact on ASMR in multivariate analysis were age of targeted population (p<0.01), disease severity (p=0.03), treatment line (p=0.04), type of clinical trial (p=0.03) and HTA date (p<0.01). CONCLUSIONS: ASMR is a complex concept which includes multiple aspects of drug value. Number of ODs remains limited which may have resulted in lack of power. Several covariates showing no statistical significance in the bivariate analysis had a significant impact on ASMR in the multivariate analysis. This may indicate the presence of unstudied interaction, unbalanced sample size or high intra group variation.