ObjectiveTo determine risk of Down syndrome (DS) in multiple relative to singleton pregnancies, and compare prenatal diagnosis rates and pregnancy outcome.DesignPopulation-based prevalence study based on EUROCAT congenital anomaly registries.SettingEight European countries.Population14.8 million births 1990–2009; 2.89% multiple births.MethodsDS cases included livebirths, fetal deaths from 20 weeks, and terminations of pregnancy for fetal anomaly (TOPFA). Zygosity is inferred from like/unlike sex for birth denominators, and from concordance for DS cases.Main outcome measuresRelative risk (RR) of DS per fetus/baby from multiple versus singleton pregnancies and per pregnancy in monozygotic/dizygotic versus singleton pregnancies. Proportion of prenatally diagnosed and pregnancy outcome.Statistical analysisPoisson and logistic regression stratified for maternal age, country and time.ResultsOverall, the adjusted (adj) RR of DS for fetus/babies from multiple versus singleton pregnancies was 0.58 (95% CI 0.53–0.62), similar for all maternal ages except for mothers over 44, for whom it was considerably lower. In 8.7% of twin pairs affected by DS, both co-twins were diagnosed with the condition. The adjRR of DS for monozygotic versus singleton pregnancies was 0.34 (95% CI 0.25–0.44) and for dizygotic versus singleton pregnancies 1.34 (95% CI 1.23–1.46). DS fetuses from multiple births were less likely to be prenatally diagnosed than singletons (adjOR 0.62 [95% CI 0.50–0.78]) and following diagnosis less likely to be TOPFA (adjOR 0.40 [95% CI 0.27–0.59]).ConclusionsThe risk of DS per fetus/baby is lower in multiple than singleton pregnancies. These estimates can be used for genetic counselling and prenatal screening.