Objectives To investigate the use of the maxilla-nasion-mandible (MNM) angle and fetal profile (FP) line to assess the degree of midfacial hypoplasia in Down-syndrome fetuses in the second and third trimesters of pregnancy. Methods The MNM angle and FP line were measured retrospectively in stored two-dimensional images or three-dimensional volumes of fetuses with Down syndrome. Data collected from January 2006 to July 2013 were retrieved from the digital databases of participating units. The MNM angle was expressed as a continuous variable (degrees) and the FP line as positive, negative or zero. Measurements were obtained from stored images in the midsagittal plane by two experienced examiners and compared with our previously reported normal ranges for euploid fetuses. A MNM angle below the 5th centile of the reference range and a positive or negative FP line were considered as abnormal. Results A total of 133 fetuses with Down syndrome were available for analysis, eight of which were subsequently excluded because of inadequate images. The MNM angle was not influenced by gestational age (P = 0.48) and was significantly smaller in Down-syndrome fetuses than in euploid fetuses (mean, 12.90° vs 13.53°, respectively; P = 0.015). The MNM angle was below the 5th centile for euploid fetuses in 16.8% of fetuses with Down syndrome (P < 0.01). In the cohort of Down-syndrome fetuses, a positive FP line was present in 41.6% of cases (with a false-positive rate (FPR) of 6.3%) and was positively correlated with Down syndrome and gestational age (P < 0.01). There was no case with a negative FP line. In cases of Down syndrome, a positive FP line was correlated with a small MNM angle (P < 0.01). Conclusions A small MNM angle and a positive FP line can be regarded as novel markers for Down syndrome. The FP line is an easy marker to measure, has a low FPR, does not require knowledge of normal reference values and has the potential to differentiate between Down syndrome and trisomy 18, as, in the latter, the FP line is often negative.