ABSTRACTObjectiveTo evaluate the usefulness of chromosome microarrays as a second‐tier test in prenatal genetic testing.MethodsWe prospectively analyzed 75 high‐risk pregnancies undergoing invasive prenatal genetic testing in which the karyotype either was normal or had findings other than a common non‐mosaic autosomal aneuploidy.ResultsChromosomal microarray analysis (CMA) was performed successfully in all cases. Pathological copy‐number variations (CNVs) explaining the phenotypes were found in 11 cases (14.7%). Four cases were detected with an unbalanced translocation. In three of these cases, subsequent genetic analysis demonstrated that a parent was an unknown carrier of a balanced translocation. Among the 67 cases with normal karyo‐types, submicroscopic rearrangements with pathological significance were detected in five (7.5%) and CNVs of unclear significance were detected in one (1.5%). CMA was able to discriminate correctly between true mosaicism and confined or pseudomosaicism in all six mosaic cases.ConclusionCMA is a valuable second‐tier test in high‐risk pregnancies for which identification or further delineation of genetic aberrations is important. Its higher resolution results in a higher detection rate of aberrant cases, with a clear clinical benefit for estimation of risk of recurrence. Copyright © 2013 ISUOG. Published by John Wiley & Sons, Ltd.