The aim of the study was to compare whether systematic strictly timed screening of all pregnancies would improve the detection of major fetal anomalies. All pregnant women (95%) from a certain area were randomly allocated for one ultrasound screening examination between the 16th and 20th weeks of gestation. Otherwise the screening (N = 4691) and control groups (N = 4619) received the same antenatal care. Screening included a systematic search for fetal anomalies. In the screening group, 40% of major fetal anomalies were detected in the screening, and 11 abortions were induced because the malformation was either lethal or severely handicapping. In the control group, 77.0% of participants had ultrasound examination any time during pregnancy. By ultrasound 13 (27%) major fetal anomalies were detected, only two of these before the 21st week of gestation. Screening detected most of the anomalies of the central nervous system and genitourinary system and cases with multiple anomalies, but was less satisfactory in detecting the anomalies of the heart and gastrointestinal tract. The perinatal mortality rate was 4.2 per 1000 in the screening group and 8.4 per 1000 in the control group (p = 0.013). The detection of major fetal anomalies in ultrasound screening can reduce perinatal mortality. A systematic search for fetal anomalies should be included in the ultrasound screening of all pregnancies.