A heart-cutting liquid chromatography-mass spectrometry (LC-MS) method was developed for the simultaneous analysis of seven process related substances (PRS) at ng ml-1 level in tablets containing cetirizine (CTZ) as active ingredient. After dissolution and filtration, 10 μl of sample was injected onto a cyano-column coupled to an electrospray ionization-mass spectrometer (ESI-MS) equipped with a single quadrupole. A switching valve placed between the analytical column and the MS detector allowed for the transfer of only the PRS fractions into the MS. The separation of PRS and CTZ was achieved in <14 min with a binary gradient using a 50 mM ammonium acetate solution (pH 7) and acetonitrile. The ESI-MS detection was performed using single ion monitoring (SIM). The method was validated. Weighted linear regression was found appropriate in a concentration range of 2.5-250 ng ml-1 and the limit of quantification (LOQ) was estimated at 10 ng ml-1 for each analyte. Method selectivity and robustness was demonstrated. Method performance was evaluated in terms of accuracy and precision using quality control (QC) samples over the investigated range. Finally, the heart-cutting LC-MS method was successfully applied to commercially available tablets.