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The aim of this study was to calculate the theoretical performance of non-invasive prenatal testing based on counting methods.The calculations were based on Gaussian distributions of the percent cell-free DNA from selected chromosome regions in affected and normal pregnancies. The means were derived from the relative genomic size of the chromosome region and the fetal fraction. The standard deviations were derived from the bivariate distributions of proportional counts. Depth of sequencing was varied from 50 000 000 to 100 000 and fetal fraction from 20% to 3%. Detection rate was estimated for a fixed 0.13% false-positive rate.When either depth or fetal fraction is high, expected Down syndrome screening detection rates are high. However, when fetal fraction is low, deeper sequencing is required to obtain high detection rates. For microdeletion and microduplication screening, deeper sequencing is routinely required to consistently achieve high detection rates. There are small differences in the ability to detect a microdeletion compared with a duplication of the same size.While the theoretical calculations do not necessarily reflect the performance of currently available non-invasive prenatal testing tests, it confirms that fetal fraction is a key factor. Efficacy can be substantially altered depending on the abnormality under investigation and the depth of sequencing. © 2014 John Wiley & Sons, Ltd.What's already known about this topic?Non-invasive prenatal testing for fetal aneuploidy can be carried out by counting the chromosome-specific cell-free DNA fragments in maternal plasma.Modeling has demonstrated the importance of the fetal fraction to discriminate Down syndrome and unaffected pregnancies.What does this study add?Depth of sequencing as well as fetal fraction are important determinants of Down syndrome screening performance.These factors are critically important in testing for microdeletion and microduplication syndromes.