Background: Public health authorities have recognized lack of hand hygiene in hospitals as one of the important causes of preventable mortality and morbidity at population level. The implementation strategy ACCOMPLISH (Actively Creating COMPLIance Saving Health) targets both individual and environmental determinants of hand hygiene. This study aims to evaluate the cost-effectiveness of a multicomponent implementation strategy aimed at the reduction of healthcare associated infections in Dutch hospital care, by promotion of hand hygiene. Methods/design: The ACCOMPLISH package will be evaluated in a two-arm cluster randomised trial in 16 hospitals in the Netherlands, in one intensive care unit and one surgical ward per hospital. Intervention: A multicomponent package, including e-learning, team training, introduction of electronic alcohol based hand rub dispensers and performance feedback. Variables: The primary outcome measure will be the observed hand hygiene compliance rate, measured at baseline and after 6, 12 and 18 months; as a secondary outcome measure the prevalence of healthcare associated infections will be measured at the same time points. Process indicators of the intervention will be collected pre and post intervention. An ex-post economic evaluation of the ACCOMPLISH package from a healthcare perspective will be performed. Statistical analysis: Multilevel analysis, using mixed linear modelling techniques will be conducted to assess the effect of the intervention strategy on the overall compliance rate among healthcare workers and on prevalence of healthcare associated infections. Questionnaires on process indicators will be analysed with multivariable linear regression, and will include both behavioural determinants and determinants of innovation. Cost-effectiveness will be assessed by calculating the incremental cost-effectiveness ratio, defined here as the costs for the intervention divided by the difference in prevalence of healthcare associated infections between the intervention and control group. Discussion: This study is the first RCT to investigate the effects of a hand hygiene intervention programme on the number of healthcare associated infections, and the first to investigate the cost-effectiveness of such an intervention. In addition, if the ACCOMPLISH package proves successful in improving hand hygiene compliance and lowering the prevalence of healthcare associated infections, the package could be disseminated at (inter) national level.