The analysis offers a new approach to the generation of economic evidence regarding the global health burden of alcohol, tobacco, and illicit drug use. The authors propose a generalized form of cost-effectiveness analysis (CEA) that is capable of producing like-with-like comparisons of the relative effectiveness and efficiency of drug abuse prevention strategies. This proposed CEA is superior to most other forms of CEA found within the research literature because it enables the comparison of interventions not only within specific diseases, but also across diseases or their risk factors. To illustrate the application of the proposed CEA, it is applied to a range of personal and non-personal interventions for reducing the global health burden of addictive substances. While the proposed CEA presented here overcomes many previous problems, the authors caution that there remain numerous challenges to population-level analyses conducted on a global level. The key policy implication arising from the analysis is that there are a number of intervention strategies that can have a significant impact on population health, including individual therapies such as nicotine replacement therapies and population-wide strategies such as the taxation of alcohol and tobacco products. It is also clear that governments can play an important role in encouraging risk reduction strategies for legal substances. The authors show how the many published studies of the cost-effectiveness of evidence-based interventions for drug use found within the research literature suffer from a series of practical problems when they are employed for sector-wide decisionmaking. Some of these practical problems include methodological differences, differences in their analytical reference points, and the degree of specificity to particular contexts. Figures, table, references