To determine whether sonographic "markers" are associated with fetal Down syndrome during the second trimester and to estimate the degree of risk of individual markers using likelihood ratios. Second-trimester (14-20 weeks) sonographic findings in 186 fetuses with trisomy 21 were compared with a control group of 8728 consecutive control fetuses. Six markers were evaluated: nuchal thickening, hyperechoic bowel, shortened femur, shortened humerus, echogenic intracardiac focus, and renal pyelectasis. Major or structural abnormalities were observed in 31 fetuses with trisomy 21 (16.7%) and 53 control fetuses (0.6%) (P< .001). Some type of sonographic finding (major abnormality, minor marker, or both) was observed in 68.8% of fetuses with trisomy 21 compared with 13.6% of control fetuses (P < .001). An isolated minor or "soft" marker was the only sonographic finding in 42 (22.6%) of 186 fetuses with trisomy 21 compared with 987 (11.3%) of 8728 control fetuses (P < .001). Nuchal thickening (P < .001; likelihood ratio, 11) and hyperechoic bowel (P < .001; likelihood ratio, 6.7) showed the strongest association with trisomy 21 as isolated markers, followed by shortened humerus (likelihood ratio, 5.1), echogenic intracardiac focus (likelihood ratio, 1.8), shortened femur (likelihood ratio, 1.5), and pyelectasis (likelihood ratio, 1.5). Echogenic intracardiac focus was the single most common isolated marker in both affected fetuses (7.1%) and control fetuses (3.9%) but carried a low risk (P= .046; likelihood ratio, 1.8). A single soft marker is commonly encountered during the second trimester among fetuses with trisomy 21. The risk of fetal Down syndrome, reflected by likelihood ratios, was determined for 6 individual markers. This information can be combined with the a priori risk to estimate the individual patient risk for fetal Down syndrome.