OBJECTIVES The use of polypills in the prevention of cardiovascular disease is mooted to reduce costs compared with current practice, yet there is very little prospectively-collected data to support this claim. The present study compares the ‘real-world’ costs of a polypill strategy against usual care among Australians with established cardiovascular disease or at high estimated cardiovascular risk.  METHODS A ‘within trial’ cost analysis from the Australian health system perspective of polypill-based care versus usual care with separate medications was conducted using data from the pragmatic randomised controlled trial Kanyini Guidelines Adherence to Polypill (Kanyini GAP) and linked health service and medication claims data. The primary outcome, estimated with generalised linear models, was mean health service and pharmaceutical expenditure, per patient per year. All costs during the trial, conducted from 2008-2012, were inflated to $AUD 2012 prices. RESULTS A statistically significantly lower mean pharmaceutical expenditure of $989 (95%CI 648 to 1331) per patient per year in the polypill arm compared to usual care (P<0.001, adjusted, excluding polypill cost). No significant differences were observed in annual non-hospital health service expenditure ($40, 95%CI -202 to 281 per patient). CONCLUSIONS This study provides evidence that a cardiovascular disease polypill strategy has the potential to produce significant cost-savings to health systems. At an estimated reimbursement cost of $1 per day for the polypill, these savings would have amounted to over $600 per patient per year. Cost-savings would accrue to patients also, given fewer prescription charges. Linking health service and medication claims data with data from a pragmatic randomised controlled trial has provided an avenue to assess the real-world cost implications of introducing this new technology into clinical practice.