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Indiana University-Purdue University Indianapolis (IUPUI) / Objective: CAD/CAM technology allows fabrication of thin lithium disilicate (LD) veneers to a LD crown substructure in place of using traditional feldspathic porcelain (FP) which has inferior mechanical properties. This project investigated the effect of different LD veneer applications to LD substructure on the biaxial flexural fatigue of LD veneer/substructure restorations. Materials/Methods: Forty-five LD discs (Ø = 120.7 mm) were fabricated that, when combined with the veneering discs, achieve final dimensions of (Ø = 121.2mm). Experimental groups were (n = 15) as follows: (1) Resin Bonded LD Veneer (RBLDV), LD veneer (Ø = 120.5 mm) adhesively cemented to LD (0.7 mm); (2) Sintered LD Veneer (SLDV), LD veneer (Ø=120.5 mm) sintered to LD (0.7 mm); (3) Sintered Feldspathic Veneer (SFV), feldspathic porcelain (FP) applied to LD discs to achieve a final dimension of (Ø = 121.2 mm). A fourth group of (1.2 mm) monolithic LD served as the control. Weibull-distribution survival analysis was used to compare the differences of the resistance to fracture after fatigue between groups. Total number of cycles were analyzed using one-way Anova (p < 0.05). Hypothesis: Adhering or sintering a thin laminate layer of LD on another LD surface would result in increased fracture resistance in comparison to sintered FP on LD. Results: The SFV group had significantly lower fatigue resistance than SLDV and RBLDV groups (p < 0.05). The RBLDV group fractures resulted in significantly more fractured fragments in comparison to the other groups. No statistical difference was observed in the number of cycles. The results also showed that the LD veneered groups presented similar resistance to fatigue as monolithic discs of the same overall dimensions. Conclusion: The hypothesis was accepted suggesting that veneering a LD substructure with a LD veneer, bonded or sintered, has increased resistance to fatigue as FP veneering material on a LD substructure. In addition, it was observed to have similar resistance to fatigue in comparison to the monolithic LD group.