Superconducting Tl2Ba2CaCu2O8 films were prepared by a two-step postdeposition anneal process under identical conditions on a number of single crystal substrates: (100) LaAlO3, (100) NdGaO3, (100) LaGaO3, (100) SrTiO3, (100) MgO, and (0001) Al2O3. The properties of the resulting Tl2Ba2CaCu2O8 films were strongly dependent on the substrate. Films on all substrates were predominantly c-axis oriented. Films prepared on LaAlO3, NdGaO3, and LaGaO3 also exhibited in-plane epitaxy, while films on MgO, Al2O3, and SrTiO3 were not aligned with the substrates. Some a-axis oriented grains of Tl2Ba2CaCu2O8 formed on NdGaO3 and both a-axis oriented grains and cracks were present on LaGaO3. Large amounts of secondary phases, as indicated by additional peaks in the x-ray diffraction scans, were observed for films on Al2O3 and SrTiO3 and smaller amounts on each of the other substrates. Depth profiling by sputtered neutral mass spectroscopy (SNMS) confirmed the presence of strong film-substrate reactions on Al2O3 and SrTiO3, and also indicated the presence of a reaction on NdGaO3. The Tc onset of the films as measured both inductively and by ac magnetic susceptibility varied depending on the substrate. The highest quality films were prepared on LaAlO3. NdGaO3 may also prove to be an acceptable substrate if the nucleation and growth of a-axis oriented Tl2Ba2CaCu2O8 grains can be eliminated. The remaining substrates appear to be less suitable due to severe film-substrate interactions, lack of epitaxial growth, or crystallographic phase changes.