In the recent years, liquid chromatography with tandem mass spectrometry has gained popularity in laboratories. This technique has a higher specificity, detects different analytes from a single specimen, measures analytes in distinct matrices, and substantially reduce analytical interference, with respect to immunoassay. The processing and preparation of biological samples are crucial in chromatography. Interferences in blood testing are usually caused by the presence of phospholipids and proteins. The main objective of this study was to improve analytical processes for drug screening by LC-MS/MS using a novel blood sample preparation method based on protein precipitation and removal of phospholipids. An evaluation was performed of a new method for the preparation of blood samples based on protein precipitation and removal of phospholipids by LC-Q-q-LIT. Limit of detection, limit of quantification and measurement range were determined for 56 molecules. The results of 11 cases were compared with those obtained using standard blood collection methods and instruments. The novel blood preparation and testing method based on LC-Q-q-LIT, a more sensitive technique, has demonstrated to yield comparable results to traditional methods. In addition, this new technique reduces turnaround time and costs.