Purpose: The aim of this study was to investigate the influence of the design and material composition of the supporting structure of a zirconia four-unit fixed partial denture (FPD) on stress distribution during in vitro loading. Materials and Methods: A three-dimensional finite element model of an all-ceramic FPD ranging from the maxillary left first premolar to second molar was constructed. The supporting structures were modeled in four versions. In version 1, the socket and rigidly fixed abutment teeth were made of a nickel-chromium (Ni-Cr) alloy. Version 2 was similar to version 1 but abutment teeth were embedded resiliently. Version 3 replaced the Ni-Cr alloy with polyurethane as the material for the socket and abutment teeth. Version 4 was designed according to the in vivo situation with a simulated periodontal ligament, the socket consisting of spongiosa, and abutment teeth composed of dentin. An occlusal force of 1,630 N was distributed over the marginal ridges of the pontics. Results: The highest tensile stresses were located within the framework underneath the connector between the second premolar and first molar and ranged between 289 and 633 MPa, according to the model version. The resilient support of abutment teeth resulted in considerably higher maximum tensile stresses. Conclusions: The choice of material for abutment teeth and the socket, as well as the type of tooth support, significantly influence stresses generated in FPDs during in vitro load tests. To achieve realistic results, FPDs should be supported by resiliently embedded abutment teeth made of a moderately rigid material (eg, polyurethane). In clinical practice, risk of failure is likely to rise with an increasing resilience of the abutment teeth if occlusal contacts are directed over the pontic/connector region rather than being spread over the retainers.