The formation and distribution of oxygen vacancy in layered multicomponent InAMO 4 oxides with A3 +=Al or Ga and M2 +=Ca or Zn and in the corresponding binary oxide constituents is investigated using first-principles density functional calculations. Comparing the calculated formation energies of the oxygen defect at six different site locations within the structurally and chemically distinct layers of InAMO 4 oxides, we find that the vacancy distribution is significantly affected not only by the strength of the metal-oxygen bonding, but also by the cation's ability to adjust to anisotropic oxygen environment created by the vacancy. In particular, the tendency of Zn, Ga, and Al atoms to form stable structures with low-oxygen coordination results in nearly identical vacancy concentrations in the InO 1.5 and GaZnO 2.5 layers in InGaZnO 4, and only an order of magnitude lower concentration in the AlZnO 2.5 layer as compared to the one in the InO 1.5 layer in InAlZnO 4. The presence of two light-metal constituents in the InAlCaO 4 along with Ca failure to form a stable fourfold coordination as revealed by its negligible relaxation near the defect, leads to a strong preference of the oxygen vacancy to be in the InO 1.5 layer. Based on the results obtained, we derive general rules on the role of chemical composition, local coordination, and atomic relaxation in the defect formation and propose an alternative light-metal oxide as a promising constituent of multicomponent functional materials with tunable properties.