OBJECTIVES: There is growing interest in the economic evaluation of pharmaceuticals at the multinational level. The purpose of these evaluations is to inform healthcare decision-makers about the cost-effectiveness of pharmaceuticals, whose interests are largely specific to their own countries. The objective of this research is to identify and critically appraise multinational economic evaluations relating to pharmaceuticals in a number of disease areas, to produce a comprehensive list of the methodological considerations and to demonstrate how previous work can inform and ensure optimal design and analysis of future multinational economic evaluations. METHODS: A systematic review involving databases (including MEDLINE, OHE, NHS) and hand-searches of journals was conducted for multinational economic evaluations. Each economic evaluation was assessed using a 70-point checklist specifically developed for multinational economic evaluations, which evaluated design issues (study question, study bias, outcomes) and analysis issues (data pooling, data presentation, data robustness and data generalisability) and also scored against a previously developed 35 point generic checklist based on the BMJ guidelines. Simultaneously a review was performed on the literature on generalisability and a survey was conducted in a number of countries to ascertain attitudes to generalisability of data from multinational clinical trials. RESULTS: 16 economic evaluations met the criteria for inclusion, which were based on a variety of frameworks and all took the form of cost-effectiveness analyses (5 = multinational clinical-economic trials, 7 = adaptation of single country clinical-economic trials and 4 = multinational decision-analytic models) With the 70-point checklist, it was found that the studies addressed different subsections of the checklist adequately and the quality of the studies showed further variation using the 35-point checklist . There were very few papers on generalisability, but the results of the survey demonstrated a degree of convergence. CONCLUSIONS: Worldwide, the issue of multinational economic evaluations is generating huge interest and is one of the biggest challenges facing health economics today. However this area has not been extensively researched and there is an urgent need for additional methodological work. This research is a first step towards developing a set of guidelines for use in future studies relating to the design, analysis and presentation of multinational economic evaluations with the purpose of maximizing the generalisability of these studies and hence their value to decision-makers.