This study evaluated the effect of a fiber-premixed indirect resin composite (FMC) substructure on the fracture resistance of mesialocclusal-distal (MOD) indirect composite restorations adhered to extracted human upper premolars. The teeth received a standardized MOD cavity preparation, and indirect composite inlays were fabricated with or without using the FMC. Inlays were cemented into the cavity preparations using either Super-Bond C&B or Panavia F2.0. A total of 28 specimens, namely seven specimens for four groups, were thus fabricated. Failure load and failure energy were determined after thermocycling (4-60 degrees C for 5,000 cycles). In terms of failure load, no significant differences were found among the four groups. In terms of failure energy, FMC substructure exerted a significantly favorable effect on Super-Bond C&B-bonded group but a negative one on Panavia F2.0-bonded group. In conclusion, the failure energy of the group using FMC substructure and which was adhered using Super-Bond C&B was significantly higher than the other groups.