Aim of this in vitro study was to investigate the effect of artificial ageing and differential abutment support on the load-bearing capacity of zirconia posterior four-unit fixed dental prostheses (FDPs). Thirty-six FDPs were fabricated using CAD/CAM technology and divided into three groups. Specimens in the first group were cemented onto tooth analogues with simulated periodontal resilience, in the second group onto a dental implant and a tooth analogue, but in the third group only onto implants. Half of the samples in each group underwent artificial ageing. Afterwards, all FDPs were loaded until bulk fracture in a universal testing machine. Load-displacement curves and forces at fracture were recorded and results were statistically analysed using ANOVA. Load-bearing capacities within the different test groups averaged as follows (control/artificially aged): tooth-tooth supported (2,009/1,751 N), tooth-implant supported (2,144/1,935 N) and implant-implant supported (2,689/2,484 N). Artificial ageing as well as differential abutment support did have a significant influence on the fracture strength of the zirconia FDPs. Implant-retained prostheses demonstrated the highest load-bearing capacity, while resilient support was demonstrated to be unfavourable. According to these in vitro results, zirconia four-unit prostheses may be promising for application in posterior areas with all three support scenarios (implant-assisted, tooth-retained, or implant-tooth-interconnected prostheses). However, the restorations' mechanical strength may expected to be significantly influenced in situ by ageing of the material on the long term.