Objective To investigate if ductus venosus (DV) pulsatility index for veins (PIV) and a-wave measurements can increase the accuracy of first-trimester Down syndrome screening in a high-risk population. Methods The database of our fetal medicine unit was searched for all cases at increased first-trimester Down syndrome risk. Multivariable logistic regression was used to construct a prediction rule for chromosomal anomalies at any given maternal age, nuchal translucency multiples of the median (NT-MoM) and DV-PIV MoM. The discriminative ability of the model was assessed by using receiver-operating characteristics (ROC) analysis. Results The study population included 445 fetuses. DV-PIV was increased (≥ 95th percentile) in 239 (54%) and DV a-wave was abnormal in 187 fetuses (42%). In this cohort, 80% of all chromosomal anomalies were identified by an increased DV-PIV and 68% by an abnormal a-wave. The odds of chromosomal anomalies increased by a factor of 4.2 per MoM increase in DV-PIV, adjusted for NT and maternal age. The area under the ROC curve for the prediction of chromosomal anomalies was 0.79. After correction for DV-PIV, DV a-wave did not significantly add to the prediction of chromosomal anomalies. Conclusion In a population of fetuses at increased first-trimester risk for Down syndrome, the combination in a logistic regression model of NT, DV-PIV and maternal age can improve the accuracy of screening for trisomy 21 and other chromosomal anomalies. This is the first study that models the additional value of DV-PIV as a continuous variable to NT measurement alone in a high-risk first-trimester population. Copyright © 2010 ISUOG. Published by John Wiley & Sons, Ltd.