This chapter analyses the appropriate use of cost-minimization analysis (CMA) as a valid and reliable method of health economic evaluation based on high-quality sources of clinical evidence with regard to the clinical equivalence between two drugs. The chapter emphasizes the manner in which CMA has previously been misused to support ‘me-too’ drugs through an inappropriate and misleading ‘assumption’ of clinical equivalence and outlines the necessary and essential clinical prerequisites required to underpin the appropriate use of this methodology. A range of practical and theoretical steps is also outlined to improve the quality of CMAs so that they can be utilized as a reliable basis for making comparisons between drugs with similar therapeutic objectives and outcomes.