The purpose of this in-vitro study was to evaluate the influence of the framework design on the durability of inlay-retained cantilever fixed dental prostheses (IR-FDPs), made from zirconia ceramic, after artificial ageing. Forty-eight caries-free human premolars were prepared as abutments for all-ceramic cantilevered IR-FDPs using six framework designs: occlusal-distal (OD) inlay, OD inlay with an oral retainer wing, OD inlay with two retainer wings, mesial-occlusal-distal (MOD) inlay, MOD inlay with an oral retainer ring, and veneer partial coping with a distal box (VB). Zirconia IR-FDPs were fabricated via computer-aided design/computer-aided manufacturing (CAD/CAM) technology. The bonding surfaces were air-abraded (50 μm alumina/0.1 MPa), and the frameworks were bonded with adhesive resin cement. Specimens were stored for 150 d in a 37°C water bath during which they were thermocycled between 5 and 55°C for 37,500 cycles; thereafter, they were exposed to 600,000 cycles of dynamic loading with a 5-kg load in a chewing simulator. All surviving specimens were loaded onto the pontic and tested until failure using a universal testing machine. The mean failure load of the groups ranged from 260.8 to 746.7 N. Statistical analysis showed that both MOD groups exhibited significantly higher failure loads compared with the other groups (i.e. the three OD groups and the VB group) and that there was no significant difference in the failure load among the OD groups and the VB group. In conclusion, zirconia IR-FDPs with a modified design exhibited promising failure modes.