The Antibiotics Smart Use (ASU) programme was introduced in Thailand as a model to promote the rational use of medicines, starting with antibiotics. The programme’s first phase consisted of assessing interventions intended to change prescribing practices; the second phase examined the feasibility of programme scale-up. Currently the programme is in its third phase, which centres on sustainability. This paper describes the concept behind ASU, the programme’s functional modalities, the development of its conceptual framework and the implementation of its first and second phases. To change antibiotic prescription practices, multifaceted interventions at the individual and organizational levels were implemented; to maintain behaviour change and scale up the programme, interventions at the network and policy levels were used. The National Health Security Office has adopted ASU as a pay-for-performance criterion, a major achievement that has led to the programme’s expansion nationwide. Despite limited resources, programme scale-up and sustainability have been facilitated by the promotion of local ownership and mutual recognition, which have generated pride and commitment. ASU is clearly a workable entry point for efforts to rationalize the use of medicines in Thailand. Its long-term sustainability will require continued local commitment and political support, effective auditing and integration of ASU into routine systems with appropriate financial incentives.