Purpose: To evaluate the accelerated fatigue resistance of thick CAD/CAM composite resin overlays luted with three different bonding methods. Materials and Methods: Forty-five sound human second mandibular molars were organized and distributed into three experimental groups. All teeth were restored with a 5-mm-thick CAD/CAM composite resin overlay. Group A: immediate dentin sealing (IDS) with Optibond FL and luted with light-polymerizing composite (Herculite XRV). Group B: IDS with Optibond FL and luted with dual-polymerizing composite (Nexus 3). Group C: direct luting with Optibond FL and dual-polymerizing composite (Nexus 3). Masticatory forces at a frequency of 5 Hz were simulated using closed-loop servo-hydraulics and forces starting with a load of 200 N for 5000 cycles, followed by steps of 400, 600, 800, 1000, 1200 and 1400 N for a maximum of 30,000 cycles. Each step was applied through a flat steel cylinder at a 45-degree angle under submerged conditions. Results: The fatigue test generated one failure in group A, three failures in group B, and no failures in group C. The survival table analysis for the fatigue test did not demonstrate any significant difference between the groups (p = 0.154). The specimens that survived the fatigue test were set up for the load-to-failure test with a limit of 4600 N. The survival table analysis for the load-to-failure test demonstrates an average failure load of 3495.20 N with survival of four specimens in group A, an average failure load of 4103.60 N with survival of six specimens in group B, and an average failure load of 4075.33 N with survival of nine specimens in group C. Pairwise comparisons revealed no significant differences (p 0.016 after Bonferroni correction). Conclusion: Within the limitations of this in vitro study, it can be concluded that although the dual-polymerizing luting material seems to provide better results under extreme conditions, light-polymerizing luting composites in combination with IDS are not contraindicated with thick restorations. Keywords: CAD/CAM, composite resin, dual-polymerizing, fatigue resistance, immediate dentin sealing, light-polymerizing, overlays