Background: Road traffic injuries (RTIs) impose a significant social and economic burden. Objectives: The objective of this study was to estimate the medical costs and economic burden caused by RTI in Iran Methods: The major components included in this study were medical costs, lost output, and indirect costs. Cost components and their values in 2011 were obtained using previous data collected during the study. A general approach that included a consideration of capital was used to calculate the cost of RTIs. Results: The economic burden of RTIs was estimated to be more than 111,000 billion Iranian rials (IRR) ($4.44 billion USD) in 2011. This cost relates only to the health sector and does not include components such as vehicle damage, lost time in accidents, and the administrative costs of insurance and police services. The estimated cost of RTIs to the health sector was about 2.18% of Iran’s total GDP in 2011. Conclusions: The medical costs and economic burden caused by RTIs in Iran clearly indicate that injuries should be a significant concern for health policymakers and medical planners.