To explore the value of prenatal ultrasonography combined with the levels of maternal serological indicators, such as serum alpha fetoprotein (AFP) and free β-subunit human chorionic gonadotrophin (free β-HCG), for screening fetal chromosomal abnormalities. Methods: The clinical data of 348 high-risk pregnant women who needed amniotic fluid karyotype analysis were collected retrospectively. All these pregnant women had undergone ultrasound examination during 11-28 gestational weeks, and the levels of AFP and free β-HCG of these pregnant women were detected during 15-21 gestational weeks. Taking the results of amniotic fluid chromosome karyotype analysis as the "gold standard", the clinical value for screening fetal chromosomal abnormalities was compared between the prenatal ultrasound examination results and the serological indicators levels. Results: There were 26 (7.5%) cases with chromosomal abnormalities by caryotype analysis in amniotic fluid, which included 13 cases with trisomy 21, 8 cases with trisomy 18, 4 cases with trisomy 13, and 1 case with chromosome fragment abnormality. There were 23 (80.9%) fetus with chromosomal abnormalities by prenatal ultrasonography in the 26 cases with chromosomal abnormalities by caryotype analysis, which included 13 cases with trisomy 21, 7 cases with trisomy 18, and 3 cases with trisomy 13. There were 21 (88.5%) fetuses with chromosomal abnormalities by serological indicators screening, which included 13 cases with trisomy 21, 6 cases with trisomy 18, and 2 cases with trisomy 13. The AUC of ROC curve of prenatal ultrasound for diagnosing fetal chromosome abnormality was 0.719, with the sensitivity of 74.3% and the specificity of 76.4%. The AUC of ROC curve of the low value of AFP MoM for diagnosing fetal chromosome abnormality was 0.632, with the sensitivity of 87.5% and the specificity of 37.9%. The AUC of ROC curve of the low value of free β-HCG MoM was 0.763, with the sensitivity of 92.5% and the specificity of 44.3%. The AUC of ROC curve of ultrasonography combined with serological indicators for diagnosing fetal chromosome abnormality was 0.842, with the sensitivity of 98.7% and the specificity of 79.3%. Conclusion: Prenatal ultrasonography combined with serological indicators detections for early screening fetal chromosomal abnormalities not only has the advantages of non-invasiveness and reproducibility, but also can increase the clinical detection rate significantly.