OBJECTIVES: Considering the pharmaceutical expenditure trend and the current economic and social context in Portugal, this study aims to: 1) analyze the national and international policy environments in Europe and US, concerning INN prescription and generic substitution, and 2) calculate the effect of generic substitution in Portugal, in terms of savings for the NHS and patients. METHODS: We conducted an international legislation review and generics market data. We estimated annual savings under the assumption of gradual increase in generics market share, and considering the difference between branded and generic medicines prices for each group of the Reference Price System (RPS). The database includes sales from Portuguese community pharmacies. RESULTS: The INN prescription is allowed in 20 countries of all 27 European countries and in all 50 US states. The generic substitution by pharmacists is allowed in 21 European countries (mandatory in 8) and in all US states (mandatory in 14). Despite the high increase from 2002, generics market share in Portugal is still below the European average, furthermore with a slowdown in its growth since 2005. The doctors prescribed 39.1% of drugs by brand name with no permission for substitution in 2009. The simulations generated savings of €120.4 million (50.8 for the NHS and €69.6 million for patients), less 11.1% of the medicines expenditure covered by the RPS. CONCLUSIONS: The market shares observed seem to reflect the different legislative frameworks. In Portugal, despite the growing share of generics, there is still a large potential market with significant opportunities of additional savings for the health system and patients, and may contribute to a higher pharmaceuticals accessibility as well to maximize therapeutic adherence.