The growth mode of layered, binary mixed oxides consisting of NiO, MgO, and CaO has been studied using low-energy electron diffraction (LEED), ion scattering spectroscopy (ISS), and NO temperature-programmed desorption (NO-TPD). The NiO/MgO layered system shows greater long-range order relative to NiO/CaO. The superior wetting found for NiO/MgO compared to NiO/CaO is likely due to the close lattice match of NiO/MgO, in contrast to NiO/CaO. The influence of MgO and CaO on NO adsorption on NiO has been studied using TPD and infrared reflection absorption spectroscopy (IRAS) and correlated with the growth mode of the corresponding layered oxide system. A long-range, substrate-mediated interaction has been found between NO and coadsorbed MgO (or CaO) on the NiO(100)/Mo(100) surface.