Background: Down syndrome (DS) screening has been integrated into prenatal care programs in Iran. Objectives: Using cost-benefit analysis (CBA) method, this study aimed to evaluate the economic aspects of combined first trimester screening in Iran. Methods: The population of this descriptive cross-sectional study included all pregnant women in Tehran, Iran. A decision tree model was used to determine the costs and benefits of diagnosing and averting a DS fetus through screening. Direct and indirect costs of diagnosis and the incremental living costs of DS children in 2019 were calculated from societal perspective and compared with each other. Results: The cost of identifying a fetus with DS in Iran is approximately equal to 611 million Tomans (about 25,000 USD), and the incremental living cost of DS children (benefits) is about 34 million Tomans (about 2,270 USD). The net monetary benefit is negative due to the lower incremental living cost of a DS child than the cost of finding the affected fetus. Conclusions: Our results showed that the cost of finding an affected fetus is more than the incremental living cost of a DS child. Also, combined first-trimester screening test for DS brought no positive net benefits in Iran.