Purpose: Conservative restorations of endodontically treated premolars have yielded mixed results. The present study aimed to compare fracture resistance of endodontically treated premolars with Class II mesial-occlusal cavity preparations, restored with either Smart Dentin Replacement (SDR; Dentsply Sirona) material, Biodentine (Septodont) or ceramic inlays. Materials and Methods: Thirty-two extracted premolars were randomly divided into four equal groups (n = 8): Group 1 served as a control group with teeth left intact; teeth in the remaining three groups received root canal treatment followed by a mesio-occlusal cavity preparation. These crowns were restored with: Biodentine in group 2, SDR in group 3 and ceramic inlays in group 4. A computer-controlled Instron universal testing machine subjected all specimens to compressive load until failure. Force at failure and fracture mode (above or below the cementoenamel junction) were recorded. The data were analysed using Fisher’s exact test and one-way ANOVA followed by the post-hoc Tukey’s test. Statistical significance was set at p < 0.05. Results: The lowest mean load at failure was recorded for the inlay group. Loads at failure were statistically significantly higher for teeth restored with Biodentine than with SDR (p = 0.012) and ceramic inlays (p = 0.007). There were no statistically significant differences between the groups in terms of fracture mode (p = 0.440). Conclusion: Endodontically treated premolars with mesial-occlusal cavity preparation restored with Biodentine were more resistant to fracture than those restored with either SDR or ceramic inlays. Biodentine may prove a promising material to restore endodontically treated teeth with one missing proximal wall.