In a growing number of laboratories the technique of liquid chromatography-tandem mass spectrometry is used for the quantification of cyclosporin A in whole blood, employing cyclosporin D as the internal standard. Cyclosporin A is extensively metabolized in vivo; in liquid chromatography-tandem mass spectrometry respective metabolites can give rise to both parent and product ions that are isobaric with ions commonly used for the detection of cyclosporin A and cyclosporin D, respectively. In this article it is demonstrated that limited chromatography with co-elution of such metabolites together with cyclosporin A and cyclosporin D can lead to incorrect results.Keywords: cyclosporin A; cyclosporin D; liquid chromatography-tandem mass spectrometry; specificity.In tandem-mass spectrometry the detection of target analytes is based on their physical decomposition behavior; the molecular mass-specific selection of an intact precursor ion of an analyte and of the respective product ion results in very high analytical specificity. This high degree of specificity can limit the requirements of sample preparation and chromatography and may enable ''high-throughput'' routine methods. However, the specificity of tandem-mass spectrometry should not be assumed to be absolute and unlimited. Given the complexity of human body fluids as a matrix and the extensive metabolization of certain target analytes, the specificity of liquid chromatography-tandem mass spectrometry (LC-MS/MS) may be a critical issue. This is demonstrated by an observation reported here.With the intention of switching the quantification of whole blood cyclosporin A (CsA) from immunoassay technology to LC-MS/MS, we decided to modify the LC-MS/MS method that we currently use for the quan-