OBJECTIVE To compare the effects, safety, and cost effectiveness of antenatal screening strategies for Down's syndrome. DESIGN Analysis of incremental cost effectiveness. SETTING United Kingdom. MAIN OUTCOME MEASURES Number of liveborn babies with Down's syndrome, miscarriages due to chorionic villus sampling or amniocentesis, health care costs of screening programme, and additional costs and additional miscarriages per additional affected live birth prevented by adopting a more effective strategy. RESULTS Compared with no screening, the additional cost per additional liveborn baby with Down's syndrome prevented was 22 000 pound sterling for measurement of nuchal translucency. The cost of the integrated test was 51 000 pound sterling compared with measurement of nuchal translucency. All other strategies were more costly and less effective, or cost more per additional affected baby prevented. Depending on the cost of the screening test, the first trimester combined test and the quadruple test would also be cost effective options. CONCLUSIONS The choice of screening strategy should be between the integrated test, first trimester combined test, quadruple test, or nuchal translucency measurement depending on how much service providers are willing to pay, the total budget available, and values on safety. Screening based on maternal age, the second trimester double test, and the first trimester serum test was less effective, less safe, and more costly than these four options.