OBJECTIVES: To investigate differences between therapeutic innovative criteria currently used in France and Italy and their implications for pricing and reimbursement. The French (Haute Autorité de Santé, HAS) and Italian (Agenzia Italiana del Farmaco, AIFA) national authorities both evaluate therapeutic innovation of new medicines as part of their drug approval process. This comparative analysis examines criteria used to assess innovation in France (Service Médical Rendu [SMR]; Amélioration du Service Médical Rendu [ASMR]) and Italy.   METHODS: Peer-reviewed literature including French and Italian reports and health technology assessment (HTA) websites were searched for publically-available records of new drugs evaluated for therapeutic innovation in France and Italy since 2010. Eighteen drugs on the Italian innovative drug list were compared against French SMR and ASMR rankings.   RESULTS: The findings of this study show similarities between the decision-making processes in each country. However, differences exist in the algorithms applied to evaluate therapeutic innovation, leading to different outcomes in each country. For example, in 2012 ipilimumab  was classified as an ‘H’ class drug (only fully reimbursed in hospitals) and ranked ‘important’ for innovation in Italy. On the other hand, in France, ipilimumab received an ‘important’ SMR score (i.e. 65% level of reimbursement) but only an ASMR score ‘IV’ for innovation (minor improvement in actual benefit in terms of therapeutic strategy). CONCLUSIONS: France and Italy currently have complex systems for determining therapeutic innovation to set clinical value and reimbursement rates. Inconsistencies between the countries may lead to disparities in access and in pricing and reimbursement of innovative medicines. Further clarification of the terminology used in each set of criteria is required in both countries. France may benefit from the implementation of a simplified new therapeutic index (e.g. Relative Therapeutic Index, new criteria proposed in 2012).