Chromosome microarray analysis (CMA) has proven to be a powerful tool in postnatal patients with intellectual disabilities, and it is increasingly used in prenatal diagnosis. However, its diagnostic capabilities in prenatal diagnosis vary, and clinical experiences have failed to establish a consensus regarding CMA indications, the design and resolution of microarrays, and the notification and interpretation of copy number variations (CNVs). We present our 5 years of clinical experience using whole-genome high-resolution single nucleotide polymorphism (SNP) arrays to investigate 446 fetuses that had structural malformations detected with ultrasound but for which standard karyotyping analysis showed normal karyotypes. CMA revealed genomic CNVs in 323 (72.4%) cases and clinically significant CNVs in 11.4% of the fetuses (51/446), including 2 cases of uniparental disomy (UPD) as well as 1 case of cryptic mosaic monosomy of chromosome X. Variants of unknown significance (VOUS) existed in 2.0% of the tested fetuses (9/446). Our results demonstrate the value of whole-genome high-resolution SNP arrays in fetuses with congenital malformations and give a higher detection rate of clinically significant genomic imbalance, especially for detecting UPD. Sufficient communication between technicians and genetic counselors, along with parental testing and comparison with data from in-house or international sources, can significantly reduce VOUS.