BACKGROUND: In France, there is a strictly regulated National Screening Programme for Down syndrome, based on second-trimester maternal serum markers. A prospective study of nuchal translucency together with retrospective evaluation of maternal serum markers was carried out to inform decisions on whether to move the programme to the first trimester. METHODS: Between January 1998 and June 2001, all women who presented for their prenatal care at 12 participating maternity units were, regardless of age, invited to provide a blood sample and to attend for an NT scan at 11 to 13 weeks. The results were used to derive Gaussian distribution parameters. Detection and false-positive rates were computed in two ways: statistical modelling and directly. The cut-off risk was 1 in 250 at term. RESULTS: A total of 5694 women with singleton pregnancies were screened including 26 with Down syndrome and 24 with other aneuploidies. The model-predicted detection and false-positive rates for combined ultrasound and serum screening were 81 and 4.5% compared to 64 and 6.0% for ultrasound alone. The directly observed rates were 73 and 4.7%, compared to 62 and 5.0% respectively. CONCLUSION: In France, first-trimester screening with nuchal translucency and maternal serum markers is likely to achieve a high screening efficiency. This has important implications for the national screening policy. Copyright 2003 John Wiley & Sons, Ltd.