Thin epitaxial Nb films on the (110) TiO 2 (rutile) have been prepared by molecular beam epitaxy at room temperature. As demonstrated by in-situ reflection high-energy electron diffraction, Auger electron spectroscopy and TEM, a structurally distorted interlayer of about 2-3nm has formed between Nb and TiO 2 in the early growth stages. The formation of the interlayer was the result of a strong chemical reaction at the interface caused by the high oxygen affinity of niobium. The first two monolayers of Nb were oxidized, resulting in the partial reduction of a ~2nm thick TiO 2 layer near the interface. On top of the interfacial reaction layer, Nb grew epitaxially with the following orientation relationship: (100)[001]Nb (110)[001] TiO 2 . In this paper we report the first direct observation of the Nb/TiO 2 interface by high-resolution transmission electron microscopy. Additionally, electron-energy loss spectra were recorded in a dedicated scanning transmission electron microscope to determine the chemical composition of the interfacial interlayer with high spatial resolution. The formation of the interlayer and the corresponding epitaxial orientation are discussed in detail.