Two common analytical chemical problems often encountered when using chromatographic techniques in drug analysis are matrix interferences and ion suppression. Common sample preparation often involves the dilution of the sample prior to injection onto an instrument, especially for liquid chromatography-mass spectrometry (LC-MS) analyses. This practice frequently does not minimize or eliminate conditions that may cause ion-suppression and therefore, suffer more from reduced method robustness. In order to achieve higher quality results and minimize possible interferences, various sample preparation techniques may be considered. Through the use of QuEChERS ("catchers"), a novel sample preparation technique used for high aqueous content samples, benzodiazepines can be extracted from biological fluids, such as blood and urine. This approach has shown increased recoveries of target compounds when using quantification by both external and internal standard. This increase in the recoveries has been attributed to a matrix enhancement and was determined through the use of the method of standard addition. While improving the overall analytical method for gas chromatography-mass spectrometry (GC-MS) analysis, it is not clear if this approach represents an overall benefit for laboratories that have both GC-MS and high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) capability. Demonstrating evidence of variable ionization (enhancement, ion source inertness, etc.), the method of quantification should be focused on in future studies.