The EPBD recast (2010/31/EC) established that Member States (MSs) must ensure that minimum energy performance (EP) requirements for buildings are set “with a view to achieve cost-optimal levels”. The Guidelines accompanying Commission Delegated Regulation established a comparative methodology framework for calculating cost-optimal levels of minimum EP requirements for buildings and building elements. MSs are required to identify reference buildings, to define energy efficiency measures (EEMs), to assess the final and primary energy need of the reference buildings before and after the application of the different EEMs, and finally to calculate the costs of the EEMs during the expected economic life cycle. The present work is focused on the application of the EC comparative methodology for a residential reference building in Italy. The aim is to verify the effectiveness of the methodology to achieve the cost-optimal levels of EP for buildings as to maximize the net present value of EEMs. A new cost optimization procedure is proposed based on a sequential searchoptimization technique. The method considers discrete building energy efficiency options (e.g. different levels of insulation), which are applied one at a time in order to find at each step a new partial optimal building. The residential reference building is selected among the Italian building-types defined in the IEE Project TABULA (2009-2012).