The present study reports on a liq. chromatog.-tandem mass spectrometry (LC-MS/MS) method development strategy supported by design of expts. (DoE) for the trace anal. of 4-dimethylaminopyridine (DMAP). The conventional approaches for development of LC-MS/MS methods are usually via trial and error, varying intentionally the exptl. factors which is time consuming and interactions between exptl. factors are not considered. The LC factors chosen for the DoE study include flow (F), gradient (G) and injection vol. (V inj) while cone voltage (E con) and collision energy (Ecol) were chosen as MS parameters. All of the five factors were studied simultaneously. The method was optimized with respect to four responses: sepn. of peaks (Sep), peak area (A peak), length of the anal. (T) and the signal to noise ratio (S/N). A quadratic model, namely central composite face (CCF) featuring 29 runs was used instead of a less powerful linear model since the increase in the no. of injections was insignificant. In order to det. the robustness of the method a new set of DoE expts. was carried out applying robustness around the optimal conditions was evaluated applying a fractional factorial of resoln. III with 11 runs, wherein addnl. factors - such as column temp. and quadrupole resoln. - were considered. The method utilizes a Phenomenex Gemini NX C-18 HPLC anal. column with electrospray ionization and a triple quadrupole mass detector in multiple reaction monitoring (MRM) mode, resulting in short analyses with a 10 min runtime. Drawbacks of derivatization, namely incomplete reaction and time consuming sample prepn., have been avoided and the change from SIM to MRM mode resulted in increased sensitivity and lower LOQ. The DoE method development strategy led to a method allowing the trace anal. of DMAP at 0.5 ng/mL abs. concn. which corresponds to a 0.1 ppm limit of quantification in 5 mg/mL mometasone furoate glucocorticoid. The obtained method was validated in a linear range of 0.1-10 ppm and presented a %RSD of 0.02% for system precision. Regarding DMAP recovery in mometasone furoate, spiked samples produced %recoveries between 83 and 113% in the range of 0.1-2 ppm.