This paper discusses a design of expts. (DoE) assisted optimization and robustness testing of a liq. chromatog.-tandem mass spectrometry (LC-MS/MS) method development for the trace anal. of the potentially genotoxic 1,3-diisopropylurea (IPU) impurity in mometasone furoate glucocorticosteroid.  Compared to the conventional trial-and-error method development, DoE is a cost-effective and systematic approach to system optimization by which the effects of multiple parameters and parameter interactions on a given response are considered.  The LC and MS factors were studied simultaneously: flow (F), gradient (G), injection vol. (Vinj), cone voltage (Econ), and collision energy (Ecol).  The optimization was carried out with respect to four responses: sepn. of peaks (Sep), peak area (Ap), length of the anal. (T), and the signal-to-noise ratio (S/N).  An optimization central composite face (CCF) DoE was conducted leading to the early discovery of carry-over effect which was further investigated in order to establish the max. injectable sample load.  A second DoE was conducted in order to obtain the optimal LC-MS/MS method.  As part of the validation of the obtained method, its robustness was detd. by conducting a fractional factorial of resoln. III DoE, wherein column temp. and quadrupole resoln. were considered as addnl. factors.