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This document presents the results of the Italian Health Economics Association (AIES) working group established to suggest guidelines on how to conduct economic evaluation studies of health programs. The document conceptualises such studies as part of health technology assessment carried out to provide guidance to the Italian National Health Service (INHS). The document aims to make available to public institutions, regulatory agencies and organizations operating in the health field a valid and feasible tool to make decisions more rational and more productive in terms of health gains. Overall, evidence-based medicine (EBM) is gaining ground and clinical decisions are increasingly taken on the basis of adequate scientific knowledge. The document suggests to extend the EBM approach to economic analysis and details how to do it in practice. The guidelines adopt the approach of the reference case which sets precise rules about major methodological decisions. Such an approach eases comparisons of results across studies and thus contributes to use them consistently in decision making. The reference case identifies the cost-effectiveness analysis, and in particular the incremental cost per Quality-Adjusted Life-Year (QALY), as the method to be used in the reference case in economic evaluations. The guidelines intend to stimulate the discussion among main actors and stakeholders who want to contribute to the development of rational governing tools for the INHS.