Noninvasive prenatal testing (NIPT) can analyze cell-free DNA of placental origin in maternal serum for trisomy 21. The detection rate is 99.5%, and the false-positive rate (FPR) is 0.2%. Noninvasive prenatal testing is recommended only for highrisk women after conventional screening. Noninvasive prenatal testing is deemed a screening modality, and invasive diagnostic testing is required for confirmation following a “positive” result. The present study was performed to evaluate NIPT by comparing 4 strategies examining cost-effectiveness and budget impacts for health care systems and parturients. A decision-analytic model was created to compare screening-related costs and consequences of NIPT implementation. The first strategy involved current practices using combined first-trimester screening (CFTS) is offered to all women at 11 to 13 weeks’ gestation. Women at high risk for DS are offered invasive diagnostic testing, via amniocentesis with fluorescence in situ hybridization and karyotyping. For strategy 2, NIPT is a second investigation after high-risk CFTS stratification. It was assumed that only women with a positive NIPT undergo invasive diagnostic testing and further counseling. Strategies 3A and 3B categorize women as high or low risk. Women 35 years or older are considered high risk and are initially offered NIPT; all others are offered CFTS, and only those considered at high risk for DS undergo NIPT. All women who are NIPT positive are referred for invasive diagnostic testing. In strategy 4, universal NIPT replaces CFTS with NIPT as the primary screening modality. All women with a positive NIPT undergo invasive diagnostic testing and counseling. Estimated costs for each strategy were those directly related to screening and accruing to government agencies and out-of-pocket costs to the woman. Outcomes included the number of DS cases detected and the number of procedure-related losses (PRLs) avoided by not performing invasive diagnostic testing. Two cost estimates for each strategy were calculated. The low estimate included costs to the health system and patients based on the current Medicare Benefits Schedule cost and the lowest estimate of patient outof-pocket costs; the high estimate was based on both Medicare costs and the highest estimates of private health care prices. Universal NIPT was the most effective strategy and detected 657 DS cases, resulting in 11 PRLs. Strategies 3A and 3B (maternal ages >35 and >40 years, respectively) were more effective than current practices for detecting DS and avoiding PRLs. Strategy 2 was less effective for DS detection, but more effective in avoiding PRLs. Five to 11 PRLs occurred with the new strategies compared with 101 PRLs for the current practice. Strategy 2 was the least expensive option. Implementing universal NIPT would cost more than 4 times the current expenditures on DS screening. The higher cost estimates were double or triple those of the low cost, with higher out-of-pocket costs for patients. Based on DS detection, the most cost-effective new strategy was 3B. Strategies 3A and 4 offered less value for money compared with current practice. Although strategy 2 was less costly and less effective for DS detection, when based on avoiding PRLs, it was the most cost-effective. Strategy 4 had the highest incremental cost per PRL avoided. The benefits of NIPT are its ability to detect a high percentage of DS cases while decreasing the number of PRLs. These advantages generate higher costs to health systems and parturients. The substitution of NIPT for CFTS would be significantly more expensive. Benefits of replacing CFTS with NIPT include an 18% increase in DS cases detected and a decrease in the overall screening positive rate from 3.8% to less than 0.42%. Additional research is necessary to confirm these results.