Antimalarial compounds ruthenoquine and methylruthenoquine were studied by X-ray absorption spectroscopy both in solid state and in solution, in normal (aqueous or CH2Cl2 solutions) and oxidative (aqueous solution with H2O, either equimolar or in large excess) conditions, to detect small changes in the coordination sphere of the ruthenium atom. Since changes in the EXAFS spectra of these compounds are quite subtle, a complete procedure was developed to assess the different sources of uncertainties in fitted structural parameters, including the use of multivariate statistic methods for simultaneous comparison of edge energy correction Delta E-0 and distances, which can take into account the very strong correlation between these two parameters. Factors limiting the precision of distance determination depend on the recording mode. In transmission mode, the main source of uncertainty is the data reduction process, whereas in fluorescence mode, experimental noise is the main source of variability in the fitted parameters. However, it was shown that the effects of data reduction are systematic and almost identical for all compounds; hence, they can be ignored when comparing distances. Consequently, for both fluorescence and transmission recorded spectra, experimental noise is the limiting factor for distance comparisons, which leads to the use of statistical methods for comparing distances. Univariate methods, focusing on the distance only, are shown to be less powerful in detecting changes in distances than bivariate methods making a simultaneous comparison of Delta E-0 and distances. This bivariate comparison can be done either by using the Hotel ling's T-2 test or by using a graphical comparison of Monte Carlo simulation results, We have shown that using these methods allows for the detection of very subtle changes in distances. When applied to ruthenoquine compounds, it suggests that the implication of the nonbinding doublet of the aminoquine nitrogen in either protonation or methylation enhances the tilt of the two cyclopentadienyls. It also suggests that ruthenoquine and methylruthenoquine are, at least partially, oxidized in the presence of H2O2, with a small decrease in the Ru-C bond length and increase in the edge energy.