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SUMMARY Statement of problem Customized glass fiber posts using CAD-CAM technology have been suggested for restoring endodontically treated teeth. However, how weakened or non-weakened roots restored with anatomical CAD-CAM posts behave under cyclic fatigue is not clear. Objective To evaluate the load-bearing capacity under fatigue (fatigue failure load [FFL], the number of cycles for failure [CFF], and survival probabilities) and fracture pattern of weakened and non-weakened roots restored with CAD-CAM fiber post and cores, metal cast-post-core, and prefabricated fiber post and resin core. Methods and Materials A total of 60 crack-free bovine incisor roots (13 mm in length) with standard geometry were obtained and randomly allocated considering the factor “root condition” in two levels (weakened and non-weakened). Thus, half of the roots were weakened to obtain a wall thickness of 0.5 mm. After that, the endodontic treatment was executed, all roots embedded with acrylic resin and the specimens randomly allocated (n=10) considering the factor “post system” in three levels (CAD-CAM: CAD-CAM milled glass-fiber post and core; MBC: metallic-based post and core; and FRC: prefabricated glass-fiber post and composite resin core). The posts were luted with a dual-cure self-adhesive luting agent. Then, all teeth received a metallic crown. An initial load of 100 N at 20 Hz for 5000 cycles was applied for the step-stress fatigue test, followed by incremental steps of 50 N for 20,000 cycles each step, up to failure. A fracture pattern analysis was performed. Results CAD-CAM fiber post (FFL: 865 N; CFF: 311,000 cycles) presented similar fatigue performance (p>0.05) to FRC (FFL: 925 N; CFF: 335,000 cycles), with 100% of repairable fractures for non-weakened roots; however, both groups presented worse performance than MBC (p0.05; FFL: 1035-1170 N; CFF: 379,000-433,000 cycles), with a high rate of catastrophic failures. Conclusions CAD-CAM fiber post presented similar fatigue performance to MBC and FRC approaches when restoring weakened roots. CADCAM was similar to FRC when restoring non-weakened roots, while MBC enhanced fatigue properties in this scenario.