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Objectives: The aim was to investigate the fatigue performance of endodontically treated (ET) molars restored by various dentin-replacing materials and material configurations. Moreover, the impact of additional adhesive treatment with glass-ionomer cement (GIC) was evaluated., Methods: 250 intact molars were collected and randomly distributed into ten groups (n = 25). After endodontic procedure standard Class I cavities were prepared and restored with different direct restorative techniques and dentin-replacing materials. Two-group were restored with either packable or flowable short fiber-reinforced composites (SFRCs). Two-group were restored by experimental fiber-reinforced GIC with and without adhesive treatment. Four-group were restored by conventional and resin-modified GICs with or without adhesive treatment. One-group was restored with a dual-cure composite resin and last group was restored with only conventional composite resin (control). Fatigue-survival was measured for all specimens using a cyclic-loading machine until fracture occurred or a number of 40.000 cycles were achieved. Kaplan-Meyer survival analysis was conducted, followed by pairwise log-rank post hoc comparisons. Fracture mode was then examined by means of optical microscopy and SEM., Results: Group restored with flowable SFRC showed significantly higher survival (p < 0.05) compared to all of the groups, except for group restored with packable SFRC (p > 0.05). Group restored with fiber-reinforced GIC had significantly (p < 0.05) higher survival rates compared to other commercial GICs. SEM demonstrated change of the fracture line when fracture reached the SFRC layer., Significance: Direct restoration of Class I in ET molars with the use of SFRCs as dentin-replacing materials demonstrated its ability to reinforce the dental structures and to increase the fatigue resistance in this specific clinical situation., Competing Interests: Conflicts of interests Author PV consults for Stick Tech - Member of GC Group in R&D and training. Other authors declare that they have no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)