Abstract Background: The economic benefits of healthcare research require study so that appropriate resources can be allocated to this research, particularly in developing countries. As a first step, we performed a systematic review to identify the methods used to assess the economic impact of healthcare research, and the outcomes. Method: An electronic search was conducted in relevant databases using a combination of specific keywords. In addition, 21 relevant Web sites were identified. Results: The initial search yielded 8,416 articles. After studying titles, abstracts, and full texts, 18 articles were included in the analysis. Eleven other reports were found on Web sites. We found that the outcomes assessed as healthcare research payback included direct cost-savings, cost reductions in healthcare delivery systems, benefits from commercial advancement, and outcomes associated with improved health status. Two methods were used to study healthcare research payback: macro-economic studies, which examine the relationship between research studies and economic outcome at the aggregated level, and case studies, which examine specific research projects to assess economic impact. Conclusions: Our study shows that different methods and outcomes can be used to assess the economic impacts of healthcare research. There is no unique methodological approach for the economic evaluation of such research. In our systematic search we found no research that had evaluated the economic return of research in low and middle income countries. We therefore recommend a consensus on practical guidelines at international level on the basis of more comprehensive methodologies (such as Canadian Academic of Health Science and payback frameworks) in order to build capacity, arrange for necessary informative infrastructures and promote necessary skills for economic evaluation studies.