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Background Currently, noninvasive prenatal testing ( NIPT) is only recommended in high-risk women following conventional Down syndrome ( DS) screening, and it has not yet been included in the Australian DS screening program. Aims To evaluate the cost-effectiveness of different strategies of NIPT for DS screening in comparison with current practice. Methods A decision-analytic approach modelled a theoretical cohort of 300,000 singleton pregnancies. The strategies compared were the following: current practice, NIPT as a second-tier investigation, NIPT only in women >35 years, NIPT only in women >40 years and NIPT for all women. The direct costs (low and high estimates) were derived using both health system costs and patient out-of-pocket expenses. The number of DS cases detected and procedure-related losses ( PRL) were compared between strategies. The incremental cost per case detected was the primary measure of cost-effectiveness. Results Universal NIPT costs an additional $134,636,832 compared with current practice, but detects 123 more DS cases (at an incremental cost of $1,094,608 per case) and avoids 90 PRL. NIPT for women >40 years was the most cost-effective strategy, costing an incremental $81,199 per additional DS case detected and avoiding 95 PRL. Conclusions The cost of NIPT needs to decrease significantly if it is to replace current practice on a purely cost-effectiveness basis. However, it may be beneficial to use NIPT as first-line screening in selected high-risk patients. Further evaluation is needed to consider the longer-term costs and benefits of screening. [ABSTRACT FROM AUTHOR]