Abstract: Objective To evaluate the diagnostic efficacy and economic value of cell-free DNA screening for newborns with trisomy 21 syndrome. Methods Pregnant women who met the research criteria for routine delivery and delivery at Wenzhou Central Hospital and Taizhou Hospital of Zhejiang Province from January 2017 to December 2018 were included in the study. They were divided into routine screening group and cell-free DNA group by random number table method. Routine triple screening tests detected the levels of free human chorionic gonadotropin, alpha-fetoprotein and free estriol at 15-20 weeks of pregnancy, and used professional calculation software to calculate the risk of maternal delivery of children with trisomy 21. Cell-free DNA screening was performed in the 15-20 weeks of pregnancy to assess the risk of maternal birth of children with trisomy 21. Amniocentesis was performed for high-risk groups with the consent of pregnant women and their families to confirm the diagnosis. The diagnostic efficacy and economic benefits of cell-free DNA screening for trisomy 21 were analyzed. Results There were no significant differences in general information such as age and gestational age between the two groups(both P>0.05). The diagnostic sensitivity of the routine screening group was 100%, the specificity was 99%, and the sensitivity of the cell-free DNA group was 100%, specificity is 100%, the false-positive rate in the cell-free DNA group is 0.00%, which was significantly lower than that in the conventional screening group by 0.85%(χ²=6.026, P=0.014). The cost of confirming a fetus in the routine screening group was 70 860.35 yuan, and the cell-free DNA group was 58 027.81 yuan. The cost/benefit value of the screening of the cell-free DNA group was 0.012, which was lower than that of the conventional screening group by 0.017. Conclusion Cell-free DNA testing has a high diagnostic efficacy in screening trisomy 21, is relatively safe and non-invasive, and has low social cost.