Analysis of drugs and metabolites in biological matrices such as blood or plasma by LC-MS is routinely challenged by the presence of large quantities of competing molecules for ionization in soft ionization sources, such as proteins and phospholipids. While the former can easily be removed by protein precipitation, pre-analytical extraction of the latter is necessary because they show very high retention in reversed-phase LC resulting in long analysis times or in ion suppression effects when not eluted before the next runs. A novel HILIC-based SPE approach, making use of silica cartridges and of acetone as organic solvent, is introduced as a potent alternative to current commercial methods for phospholipid removal. The methodology was developed and tested for a broad polarity range of pharmaceutical solutes (log P from 0 to 6.6) and broad applicability can therefore be envisaged.