Objective: This study was undertaken to examine the cost-effectiveness and procedural-related losses associated with 5 prenatal screening strategies for fetal aneuploidy in women under 35 years old. Study design: Five prenatal screening strategies were compared in a decision analysis model: triple screen: maternal age and midtrimester serum alpha-fetoprotein, human chorionic gonadotropin (hCG), and unconjugated estriol; quad screen: triple screen plus serum dimeric inhibin A; first-trimester screen: maternal age, serum pregnancy-associated plasma protein A and free β-hCG and fetal nuchal translucency at 10 to 14 weeks' gestation; integrated screen: first-trimester screen plus quad screen, but first-trimester results are withheld until the quad screen is completed when a composite result is provided; sequential screen: first-trimester screen plus quad screen, but the first-trimester screen results are provided immediately and prenatal diagnosis offered if positive; later prenatal diagnosis is available if the quad screen is positive. Model estimates were literature derived, and cost estimates also included local sources. The 5 strategies were compared for cost, the numbers of Down syndrome fetuses detected and live births averted, and the number of procedure-related euploid losses. Sensitivity analyses were performed for parameters with imprecise point estimates. Results: In the baseline analysis, sequential screening was the least expensive strategy ($455 million). It detected the most Down syndrome fetuses (n = 1213), averted the most Down syndrome live births (n = 678), but led to the highest number of procedure-related euploid losses (n = 859). The integrated screen had the fewest euploid losses (n = 62) and averted the second most Down syndrome live births (n = 520). If fewer than 70% of women diagnosed with fetal Down syndrome elect to abort, the quad screen became the least expensive strategy. Conclusion: Although sequential screening was the most cost-effective prenatal screening strategy for fetal trisomy 21, it had the highest procedure-related euploid loss rate. The patient's perspective on detection versus fetal safety may help define the optimal screening strategy. © 2004 Elsevier Inc. All rights reserved.