Objectives The present study was performed to examine the utility of a new first trimester marker called the "brain angle" (BA) in screening for trisomy 21. We postulate that differences in the midbrain anatomy between euploid fetuses and those that are affected by trisomy 21 are reflected in changes in BA measurements. Methods In fetuses at 11(+0)-13(+6) weeks of gestations, which were at high risk for trisomy 21, the angle was measured between the line crossing the thalamus and mesencephalon cranial border tangentially and the line crossing the brainstem lower limit. This angle was compared between fetuses with trisomy 21 (based on karyotyping) and those with a normal karyotype. Results Trisomy 21 was detected in 45 (8%) of 560 fetuses. Receiver operating characteristic analysis showed that, at BA >= 94 degrees, the sensitivity and specificity for determining trisomy 21 were 97.8% (95% CI=88.2-99.9%) and 100% (95% CI=99.2-100%), respectively. Conclusions Fetal BA appears to be a promising new first trimester marker in screening for trisomy 21.