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Abstract Background Non-communicable diseases are imposing a considerable burden on Iran. This study aims to assess the Return on Investment (ROI) for implementation of Non-communicable diseases (NCDs) prevention program in Iran. Methods Four disease groups including cardiovascular diseases, diabetes, cancer, and respiratory diseases were included in our ROI analysis. The study followed four steps: 1) Estimating the total economic burden of NCDs using the Cost-of-Illness approach. 2) Estimating the total costs of implementing clinical and preventive interventions using an ingredient based costing at delivering level and a program costing method at central level.3) Calculating health impacts and economic benefits of interventions using the impact measures of avoided incidence, avoided mortality, healthy life years (HLYs) gained, and avoided direct treatment costs. 4) Calculating the ROI for each intervention in 5- and 15- year time horizons. Results The total economic burden of NCDs to the Iranian economy was IRR 838.49 trillion per year (2018), which was equivalent to 5% of the country’s annual Gross Domestic Product (GDP). The package of NCD will lead to 549 000 deaths averted and 2 370 000 healthy life years gained over 15 years, and, financially, Iranian economy will gain IRR 542.22 trillion over 15 years. The highest ROI was observed for the package of physical activity interventions, followed by the interventions addressing salt, tobacco package and clinical interventions. Conclusions NCDs in Iran are causing a surge in health care costs and are contributing to reduced productivity. Those actions to prevent NCDs in Iran, as well as yielding to a notable health impact, are giving a good economic return to the society. This study underscores an essential need for establishment of a national multi-sectorial NCD coordination mechanism to bring together and strengthen existing cross-agency initiatives on NCDs.