INTRODUCTION:Teeth fracture resistance is affected by cavity design and restorative material. Furthermore, combining ceramic and polymer phases yielded materials with improved properties that can be used for CAD/CAM fabrication of indirect restorations. OBJECTIVE: To evaluate the effect of different cavity designs and different CAD/CAM materials on fracture resistance and mode of fracture of maxillary premolars. METHODS: Forty-five sound human maxillary premolars were used. Nine specimens were left intact as control group (Group I). The rest were divided into two groups (n=18); MOD inlay (Group II) and MOD onlay (Group III). Each group was subdivided into two subgroups (n=9) according to the materials used; VITA Enamic (VE) and Lava Ultimate (LU). Cementation was done by self-adhesive resin cement RelyX™ U200. Specimens were subjected to thermocycling and fracture resistance test was done using a universal testing machine. Mode of fracture was detected by stereomicroscope. Data was analyzed using Two Way ANOVA and Tukey's test. Fracture mode was compared using Monte Carlo simulation of Pearson Chi Square test. RESULTS: Statistical significant difference was found between control group and VE onlays and LU onlays, without any significant difference among other groups. Fracture in restoration only was shown mostly in the onlays while VE inlays demonstrated fracture in both restoration and tooth structure and most LU inlays showed fracture in both restoration and tooth structure and through the long axis. CONCLUSIONS: Inlays showed the highest fracture resistance. Vita Enamic and Lava Ultimate showed comparable results regarding fracture resistance, regardless of the preparation design.