Aim: this study was to determine influence of different restorative protocols on fracture resistance of maxillary premolars with MOD cavities. Materials & Methods: three direct resin-based composites were used in this study; sonically activated bulk-fill resin composite (Sonic-fill TM Kerr, USA), short fiber-reinforced composite, everX-Posterior (G.C., Tokyo, Japan), and nanoceramic resin-based composite, Ceram.X® one (DENTSPLY, Germany). An indirect CAD/CAM composite block Grandio Blocs (VOCO GmbH, Germany) was also used. Sixty extracted maxillary premolars were collected. According to restorative protocol tested, premolars were randomly divided into six groups (ten each) and stored at room temperature in distilled water containing 0.2% sodium azide for three months. Results: One-Way ANOVA followed by Tukey's post-hoc test showed a statistically significant difference between study groups (P < 0.001). The positive control, Grandio blocs (IGG), and Ever-X- posterior (BEG) groups yielded the significantly highest mean values for maximum load. The mean value of the Sonic-fill (BSG) group did not differ from those of the IGG and BEG groups. Ceram-X-one (NCG) group had a substantially lower mean value than the positive control, IGG, BEG, and BSG groups, but a greater mean value compared to the negative control group. The negative control produced the lowest mean value among all study groups. Conclusion: The current results illustrated that the fracture resistance of maxillary premolars with MOD cavities is highly dependent on the restorative material used. Accordingly, by selecting the suitable restorative material, the restored tooth can be reinforced to a level comparable to that of a sound tooth.