The increase of computational environments dedicated to the simulation of nanoparticles (NP)-X-Rays interactions has opened new perspectives in computer-aided-design of nanostructured materials for biomedical applications. Several published studies have shown a crucial need of standardization of these numerical simulations. That is why, a robustness multi- variate analysis was performed in this paper. A gold nanoparticle (GNP) of 100 nm diameter was selected as a standard nano-system activated by a X-ray source placed just below the NP. Two response variables were examined: the dose enhancement in seven different spatial regions of interest around the NP and the duration of the experiments. 9 factors were pre-identified as potentially critical. A Plackett-Burman design of numerical experiments was applied to estimate and test the effects of each simulation factors on the examined responses. Four factors: the working volume, the spatial resolution, the spatial cutoff and the computational mode (parallelization) do not significantly affect the dose deposition results and none except the last one may reduce the computational duration. The energy cutoff may cause significant variations of the dose enhancement in some specific regions of interest: the higher the cutoff, the closer the secondary particles will stop from the GNP. By contrast, the Auger effect as well as the choice of the physical medium and the fluence level clearly appear as critical simulation parameters. Consequently, these four factors may be compulsory examined before comparing and interpreting any simulation results coming from different simulation sessions.