Several guidelines on cost-effectiveness analysis (CEA) already exist. There are two reasons for producing another set. The first is that traditional or, incremental, CEA ignores the question of whether, the current mix of interventions represents an efficient use of resources. Secondly, the resources required to evaluate the large number of interventions required to use CEA to identify opportunities to enhance efficiency are prohibitive. The approach of Generalized CEA proposed in this Guide seeks to provide analysts with a method of assessing whether the current as well as proposed mix of interventions is efficient. It also seeks to maximize the generalizability of results across settings. The Guide, in Part I, begins with a brief description of Generalized CEA and how it relates to the two questions raised above. It then considers issues relating to study design, estimating costs, assessing health effects, discounting, uncertainty and sensitivity analysis, and reporting results. Detailed discussions of selected technical issues, and applications are provided in a series of, background papers, originally published in journals, but included in this book for easy reference in Part II. The Guide and these papers, are written in the context of the work of WHO-CHOICE: CHOosing Interventions that are Cost-Effective. WHO-CHOICE is assembling regional databases on the costs, impact on population health and cost-effectiveness of, key health interventions using standardized methodology and tools. WHO-CHOICE tools on costing (CostIt(c)), population effectiveness modelling (PopMod(c)) and probabilistic uncertainty analysis (MCLeague(c)) are included in the accompanying compact disc.