Adsorption effects in the chromatographic system and/or ion source may play a very important role in the ionization processes of liquid chromatography/mass spectrometry. They have been illustrated and considered as matrix effects extensively. These effects cannot be simply removed by any thorough cleaning of the system and/or by perfecting the chromatography. The use of isotopically labeled internal standards (isotope dilution technique) is the only effective compensation for their negative impacts. The complete effectiveness of the method was presented by the evaluation of normalized matrix factor (according to the European Medicines Agency) in 85 different high-performance liquid chromatography tandem mass spectrometry methods for determination of drugs in human plasma. On the other hand, the adsorption effect of methylamine was successfully used for the determination of lacidipine in human plasma at the low picogram level.