The defect structure of epitaxial, c-oriented Bi2Sr2Can−1CunO4+2n+δ (BSCCO) thin films grown by dc-sputtering and layer-by-layer MBE on SrTiO3 and LaAlO3 single crystal substrates was investigated by high-resolution transmission electron microscopy (HRTEM). Particular emphasis was put on the structure of the film/substrate interface. The films grown by dc-sputtering show a rather perfect structure involving a regular stacking of the unit cells. In spite of this regularity, there are many defects, such as twins, chemical stacking faults, and precipitates, as well as interfacial dislocations accommodating the film/substrate lattice misfit. The MBE-grown films contain twins and interfacial dislocations, but most prominent are precipitates of various size and rather high number density. Composition and structure of the precipitates were analyzed. Interfacial dislocations were found to be located in the films at a distance of up to 3 nm from the film/substrate interface. The experiments showed that the quality of the film/substrate interface in MBE-grown films is considerably higher with respect to smoothness, sharpness, and regularity, if the layer-by-layer MBE process starts with a Sr–O layer instead of a Bi–O layer. This observation is in correspondence to the observed interface structure of the dc-sputtered films, where the first film layer was a Sr–O layer, not a Bi–O layer, in spite of the films being sputtered from a composite target. A structure model of the Bi2Sr2Can−1CunO4+2n+δ/(100)SrTiO3 interface is proposed. The prolonged MBE process was shown to imply a chemical interaction between the SrTiO3 substrate and the growing film, resulting in the formation of Sr-rich phases in the near-interface substrate regions.