OBJECTIVES To compare dipeptdyl-peptidase 4 inhibitors (DPP4i) and sulfonylurea (SU) for the treatment of type II diabetes mellitus in terms of economic impact and considering both the Italian National Health System (NHS) and the societal perspective. METHODS The economic evaluation was performed as a model-based cost-minimization analysis for the comparison DPP4i and SU as second line therapy, in add-on to metformin, over 1-year period. Clinical events to be included in the model were selected from literature review and the opinion of a panel of clinical experts. Resources used were quantified and valued adopting costs and tariffs related to drugs used, glycaemic auto-monitoring, established control visits, incidence of hypoglicaemic events, macrovascular complications and the switch to insulin therapy. One-way sensitivity analyses for model inputs were conducted. RESULTS Due to the higher cost for drug acquisition in the base case analysis total direct costs for the Italian NHS were about 728 Euro per patient/year in the case of DPP4i and on average 702 Euro for SU. The overall yearly cost for the society was estimated to be about 728 Euro per patient in the case of DPP4i while it was on average 770 Euro when considering SU because DPP4i induced lower direct non-health costs related to stroke and an overall saving of 20.88 Euro per patient/year due to lower costs of productivity loss for hypoglicaemic events and stroke. CONCLUSIONS The use of DPP4i was cost-saving from the societal perspective and just the high cost for drug acquistion made the adoption of DPP4i more costly than SU for the Italian NHS. This result outlined that DPP4i represents a valuable alternative for the management of diabetes both from a clinical and economic perspective and costs will be lowered overall just intervening on cost for drug acquisition.