Fetuses with Down's syndrome are more likely than normal fetuses to have a thickened nuchal skin fold and relatively short femurs on ultrasound examination in the second trimester. We evaluated these measures in more than 5500 fetuses, including 28 who were later found to have Down's syndrome by means of amniocentesis with cytogenetic analysis. Normal femur length was established as a function of biparietal diameter in 192 of the normal fetuses. We found that with use of a nuchal skin-fold thickness of 6 mm or more and a ratio of actual to expected femur length of 0.91 or less, fetuses with Down's syndrome could be identified with a sensitivity of 75 percent and a specificity of 98 percent. When other anomalies, such as an atrioventricular canal and meconium peritonitis, were added to these two criteria, the sensitivity of sonographic detection of Down's syndrome in the second-trimester fetus rose to 82 percent. The potential predictive value of these sonographic signs far exceeds that of advanced maternal age and low alpha-fetoprotein levels, which currently identify only 10 to 30 percent of affected fetuses. We recommend that fetuses with a thickened nuchal skin fold or shortened femurs on ultrasound examination be evaluated for Down's syndrome by amniocentesis and cytogenetic analysis.