ObjectivesThe aim of this in vitro study was to investigate the fatigue survival and fracture behavior of endodontically treated (ET) premolars restored with different types of post-core and cuspal coverage restorations.Materials and methodsMOD cavities were prepared on 108 extracted maxillary premolars. During the endodontic treatment, all teeth were instrumented with rotary files (ProTaper Universal) to the same apical enlargement (F2) and were obturated with a matched single cone obturation. After the endodontic procedure, the cavities were restored with different post-core and overlay restorations (n = 12/group). Three groups (A1–A3) were restored with either conventional composite core (PFC; control) or flowable short-fiber-reinforced composite (SFRC) core with/without custom-made fiber posts and without overlays. Six groups had similar post-core foundations as described above but with either direct PFC (B1–B3) or indirect CAD/CAM (C1–C3) overlays. Fatigue survival was tested for all restorations using a cyclic loading machine until fracture occurred or 50,000 cycles were completed. Kaplan-Meyer survival analysis was conducted, followed by pairwise post hoc comparisons.ResultsNone of the restored teeth survived all 50,000. Application of flowable SFRC as luting-core material with fiber post and CAD/CAD overlays (Group C3) showed superior performance regarding fatigue survival (p < 0.05) to all the other groups. Flowable SFRC with fiber post and direct overlay (Group B3) showed superior survival compared to all other direct techniques (p < 0.05), except for the same post-core foundation but without cuspal coverage (Group A3).ConclusionsCustom-made fiber post and SFRC as post luting core material with or without cuspal coverage performed well in terms of fatigue resistance and survival when used for the restoration of ET premolars.Clinical relevanceThe fatigue survival of direct and indirect cuspal coverage restorations in ET MOD premolars is highly dependent on whether the core build-up is fiber-reinforced or not. The combination of short and long fibers in the form of individualized post-cores seems to offer a favorable solution in this situation.