Objective. To evaluate the clinical value of a high-resolution whole-genome array method for examination of genomic imbalances in prenatal samples (46 amniotic fluid, 17 chorionic villus, and 26 products of conception) from fetuses with abnormal ultrasound, in a clinical setting where more than 90% of pregnant women receive first-trimester combined screening and a second-trimester anomaly scan. Design. Cross-sectional study. Setting. Fetal medicine units (national healthcare system) in Central and North Denmark Regions from March 2009 to April 2012. Samples Eighty-nine samples obtained at 11.5-35.0 (mean 19.3) gestational weeks, either during ongoing pregnancy or after termination. Methods. DNA was extracted directly from amniotic fluid cells and chorionic villus samples, or from cultured cells, and examined with 80-kb resolution oligonucleotide array-based comparative genomic hybridization (aCGH). Main outcome measures. Clinically significant copy number variations identified by aCGH. Results. We detected clinically significant copy number variations in 11 fetuses (12%, confidence interval 6.0-19%) with structural malformations. Three fetuses (3.4%) had uncertain clinical significant variations and incidental findings. Conclusions. aCGH is a valuable diagnostic tool when fetal malformations are detected. More affected fetuses may be diagnosed at an earlier gestational age providing better possibilities for postnatal treatment and allowing for women to decide earlier on termination of pregnancy. When a normal result has reduced the risk of significant chromosomal aberration, aCGH may facilitate parental decision-making on whether to continue the pregnancy.