INTRODUCTION: The 'Use of a Multi-drug Pill in Reducing cardiovascular Events' (UMPIRE) trial was a randomised controlled clinical trial evaluating the impact of a polypill strategy on adherence to indicated medication in a population with established cardiovascular disease (CVD) of or at high risk thereof. The aim of Researching the UMPIRE Processes for Economic Evaluation in the National Health Service (RUPEE NHS) is to estimate the potential health economic impact of a polypill strategy for CVD prevention within the NHS using UMPIRE trial and other relevant data. This paper describes the design of a modelled economic evaluation of the impact of increased adherence to the polypill versus usual care among the UK UMPIRE participants. METHODS AND ANALYSIS: As recommended by the International Society for Pharmacoeconomics and Outcomes Research and the Society for Medical Decision Making modelling guidelines, a review of published CVD models was undertaken to identify the most appropriate modelling approach and structure. The review was carried out in the electronic databases, MEDLINE and EMBASE. 40 CVD models were identified from 57 studies, the majority of economic models were health state transition cohort models and individual-level simulation models. The findings were discussed with clinical experts to confirm the approach and structure. An individual simulation approach was identified as the most suitable method to capture the heterogeneity in the population at CVD risk. RUPEE-NHS will use UMPIRE trial data on adherence to estimate the long-term cost-effectiveness of the polypill strategy. DISSEMINATION: The evaluation findings will be presented in open-access scientific and healthcare policy journals and at national and international conferences. We will also present findings to NHS policy makers and pharmaceutical companies.