OBJECTIVES: Given that vaccination systems vary widely between countries, we investigated the cost implications of different ways of organising vaccine provision in order to identify best practices METHODS: We evaluated vaccination systems in six EU countries by investigating the provision of several paediatric and adult vaccines. We validated our findings through interviews with academics, country experts and executives from large vaccine manufactures. We built a tool to simulate the impact of alternative policies on all cost components relevant in vaccine provision. RESULTS: Our findings suggest that vaccine procurement, distribution and administration are the three key areas for potential efficiency gains for vaccine provision. While procurement through tenders requires careful planning and preparation, it does seem to be an effective, short-term method for healthcare payers to obtain lower vaccine purchase prices. Policy makers may, however, need to consider that anticipated savings can be partly offset by increased wastage due to over-ordering and losses in social contributions. Examples from the six investigated countries confirm these cost components can become relevant. The main economical benefits may lie further downstream: i.e. in a more efficient provision of vaccines through alternative distribution and vaccine administration channels. Distribution can be organised directly to pharmacies or vaccinators by specialised cold chain logistics providers (such as for childhood vaccine distribution in UK) while the number and types of vaccinations settings can be extended to non-traditional settings such as schools (Belgium), pharmacies (Ireland), and vaccination centres (Greece). Based on “what-if simulations”, common efficiency gains of €10 to €15 per vaccination might be achieved in distribution and administration. CONCLUSIONS: By applying best practices in the distinct areas of vaccine procurement, distribution and administration, vaccine provision can be organised in a more cost-effective way. Policy makers should take these into consideration when choosing a specific practice for vaccine provision.