To assess the performance of sonography in the detection of fetal nonchromosomal abnormalities using a standard anatomic examination protocol proposed by International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) at 11-13 weeks. A prospective observational study was conducted between June 2013-May 2017 in singleton pregnancies attending for a routine scan at 11-13 weeks. All examinations were performed by maternal-fetal medicine specialists certified by the Fetal Medicine Foundation according to the anatomic examination protocol described in the ISUOG guidelines. First-trimester findings were compared to those of the anomaly scan at 20-23 weeks and the postnatal examination. The primary outcome was the detection rate of major structural abnormalities in fetuses with normal karyotype at 11-13 weeks. After excluding 17 chromosomal abnormalities, major fetal structural defects were detected in 57 (1.7%) of the remaining 3361 cases. Of these, 27 (47.3%) were detected at 11-13 weeks, including all cases of acrania (4), exomphalos (4), megacystis (2) and body stalk anomaly (2). Furthermore, there was a first-trimester diagnosis in 36.4% (4/11) of major cardiac defects, 38% (6/16) of limb defects, and 100% (2/2) of facial clefts. Targeted ultrasound examination may identify all the so called "always" detectable major abnormalities and a significant proportion of the "sometimes", detectable at 11-13 weeks.