Background and Aim: The present study aimed at determination of the fatigue resistance and failure mode of cuspreplacing onlays in endodontically treated premolars using indirect composite resin restorations. Materials and Method: In this experimental study, 84 human premolars were randomly divided into 7 groups of 12. These groups were prepared as follows: Intact teeth used in groupl as control, the second group covers the endodontically treated teeth, restored with indirect onlays using Z-250 composite resin, the next two groups (i.e. 3,4) were similar to the second group, but subjected to 1 and 2 million fatigue load cycles, respectively. Groups 5, 6, 7 were similar to groups 2, 3, 4, respectively, however, in these groups Tetric Ceram used as the restorative material. All specimens were loaded using a Universal Testing Machine until fracture occurred and the mode of failure observed with naked eye. Kruskal-Wallis and Chi-Square tests were used to analyze the data (a=.05). Results: All specimens withstood the masticating simulation. The mean fracture strength for groups 1 to 7 were: 1276.92, 1269.05, 1217.80, 1188.13, 1228.97, 1127.86, 1105.58, respectively. No statistically significant differences were found between the groups in fracture strength and failure mode. There was no statistically significant difference between two types of resin composite (P=0.203) and load cycles (P=0.298) after zero, 4 and 8 years aging. Conclusion: Within the limitation of this study, restored premolars with indirect composite onlays show fatigue resistance equal to natural tooth up to 8 years after restoration. Furthermore, no statistically significant differences were found between 4 and 8 years of load cycles. Tetric Ceram Z-250 restoration agent showed no effect on the tooth fracture resistance with the most observed fractures to be occur under CEJ with no capability to be restored.