High-precision Fe isotope abundance ratios find wide application in environmental geochemistry, isotope metallomics, bioarchaeology, and biomedical research, since the slightest deviation of 56Fe/54Fe and 57Fe/54Fe can provide information on their source, processing, or physiology. However, the routine adoption of high-precision Fe isotope ratio measurements is currently limited by spectrally related interferences, matrix-related mass biases, procedural blanks, incomplete recovery, and the lengthy procedure involved in the chromatographic purification step. Nitrogen plasma MC-MICAP-MS technology circumvents Ar-related polyatomic interference generation at the ion source and permits routine low-resolution determination of Fe isotope ratios after automated purification. The current bottleneck is how to make the best decision on the least intensive preparation needed for each particular sample, so that the requirements in terms of isotope ratio accuracy and expanded uncertainties are met. The uncertainty-based approach towards a decision-making tool, based on validation of the maximum tolerances for Fe, Ca, K, Na, and Mg, alongside procedural blank, Fe recovery, instrument stability, control of Cr/Ni ratios, and mass-dependence isotope pairs, provides the Purification Necessity Index (PNI). According to the PNI, Fe samples are assigned to either direct Fe measurement, verifiable measurement, or Fe measurement after dual-column chromatographic purification. Based on nitrogen plasma Fe isotope validation data, it is found that formation of CaN+ and KN+ sets stringent limits on matrix effects, while Na and Mg have looser limits for the range of tested matrices/Fe levels. The analysis of results obtained with a set of reference materials proves δ57Fe/54FeIRMM014 − δ56Fe/54FeIRMM014 as an effective tool for internal checks of non-mass-dependent deviations. The developed matrix tolerance model for Fe biological materials, environmental waters, and transient-signal isotope-metallomics applications.