While cation replacement has long been used to tailor the functionalities of oxide compounds, the growing industrial demand for nanoscale materials nowadays requires precise atomic scale characterization and understanding of the cation distribution. We report a successful synthesis and characterization of the two-dimensional (V,Fe)2O3 alloy supported on Pt(111) which is thermodynamically stable at realistic temperatures and for Fe contents up to 50%. Tight synergy between fine atomic resolution STM experiments and DFT calculations has revealed an unequivocal preference for formation of mixed V-Fe nearest-neighbor pairs, to a large extent driven by cation-cation electrostatic interactions. Moreover, Monte Carlo simulations have enabled an in-depth rationalization of the observed cation distribution in the honeycomb lattice. We show that the V-Fe mixing is restricted to 2D systems and not observed in the corresponding bulk systems, and that it is closely related to a change in vanadium oxidation state resulting from the interaction with the substrate. The flexibility of composition, of the distribution of cations and of their charge state provide levers to tune the properties of such two-dimensional oxide alloys and may thus enhance their potential for applications.