Controlled clinical trials are recognized as the best source of data on the efficacy of health care interventions. Because economic evaluation is dependent on the quality of the underlying medical evidence, clinical trials have increasingly been viewed as the natural vehicle for economic analysis. However, the closer integration of economic and clinical research raises many methodological issues. This paper discusses these issues in trial design, collection of resource use and outcome data, and the interpretation of results. Suggestions are made for resolving the major problems.