Abstract Aims The aim of this study was to estimate the cost-effectiveness, from the perspective of the Australian public healthcare system, of icosapent ethyl in combination with statin therapy compared with statin alone for the prevention of cardiovascular disease. Methods and results A Markov model populated with data from the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial was designed to predict the effectiveness and costs of icosapent ethyl in combination with statins compared with statins alone over a 20-year time horizon. Data inputs for costs and utilities were sourced from published sources. The annual costs of icosapent ethyl were assumed to be AUD1637 (USD2907) per person. All future costs and outcomes were discounted annually by 5%. The main outcome of interest was incremental cost-effectiveness ratios in terms of cost per quality adjusted life year (QALY) gained and per year of life saved (YoLS). Over a 20-year time horizon, compared with statin alone, icosapent ethyl in combination with statin was estimated to cost an additional AUD$13,022 per person, but led to 0.338 YoLS and 0.289 QALYs gained (all discounted). These equated to incremental cost-effectiveness ratios of AUD45,036 per QALY gained and AUD38,480 per YoLS. Sub-analyses for primary and secondary prevention were AUD96,136 and AUD35,935 per QALY gained, respectively. The results were sensitive to time-horizon, age related trends and the acquisition price of icosapent ethyl. Conclusion Compared with statin alone, icosapent ethyl in combination with statin therapy is likely to be cost-effective in the prevention of cardiovascular disease assuming a willingness-to-pay threshold of AUD50,000 per QALY gained, especially in the secondary preventive setting.