First-trimester screening for Down syndrome has been proposed as a significant improvement with respect to second-trimester serum screening programs, the current standard of care, because of apparently higher detection rates and an earlier gestational age at diagnosis. First-trimester nuchal translucency on ultrasonography forms the basis of this new form of screening, although studies of its efficacy have yielded widely conflicting results, with detection rates ranging from 29% to 91%. Studies of first-trimester serum screening with measurements of pregnancy-associated plasma protein A and free beta-human chorionic gonadotropin serum concentrations have been much more consistent, with Down syndrome detection rates of 55% to 63% at a 5% false-positive rate. The combination of first-trimester ultrasonographic and serum screening has the potential to yield a Down syndrome detection rate of 80% at a 5% false-positive rate, although this approach has not been adequately studied. There have been no studies performed to date to directly compare the performance of first-trimester and second-trimester methods of screening. Two major trials are underway that will address this issue, one in the United Kingdom and one in the United States. Until the results of these trials are available, the current standard of care with respect to Down syndrome screening should not be changed, and first-trimester screening should remain investigational.