Purpose: The purpose of the current study was to evaluate the effect of different CAD/CAM materials and different occlusal thicknesses on the fatigue resistance of occlusal veneers. Materials and Methods: Thirty intact maxillary molars were cut occlusally 4.0 mm above the cemento-enamel junction (CEJ). All teeth were dispersed into 3 main groups (n=10) rendering to the CAD/CAM materials tested; Lithium Disilicate (UP.Cad), Vita Suprinity (VS) and Vita Enamic (VE). Each group were further subdivided into 2 subgroups (n = 5) rendering to restoration thickness (1.0 and 1.5 mm). The restorations were adhesively bonded. Samples were subjected to step fatigue resistance test. Assessment of fracture mode was evaluated by Digital microscope. Scanning electron microscope (SEM) was used for fractographic analysis. Results: The highest fatigue resistance was recorded for VS followed by UP.CAD while the least mean value recorded with VE, the difference between groups was statistically significant (P= 0.0003<0.05) as indicated by two-way ANOVA. Occlusal veneers with 1.5 mm thickness recorded statistically significant higher fatigue resistance mean value than 1mm for all tested materials, (P= 0.0005<0.05) as indicated by two-way ANOVA. Most of the fractures were repairable patterns. Conclusions: The material type and occlusal thickness changes significantly affected the fatigue resistance of occlusal veneers. The fatigue resistance of the tested CAD/CAM materials seems promising also in 1.00mm occlusal thickness.