Purpose: To evaluate the effect of different surface treatments on the microtensile bond strength (μTBS) of novel CAD/CAM restorative materials to self-adhesive resin cement. Materials and Methods: Two types of CAD/CAM restorative materials (Vita Enamic [VE] and Lava Ultimate [LU]) were used. The specimens were divided into five groups in each test according to the surface treatment performed; Gr 1 (control; no treatment), Gr 2 (sandblasted [SB]), Gr 3 (SB + silane [S]), Gr 4 (hydrofluoric acid [HF]), and Gr 5 (HF + S). A dual-curing self-adhesive resin cement (Bifix SE [BF]) was applied to each group for testing the adhesion after 24 h of storage in distilled water or after 30 days using the μTBS test. Following fracture testing, specimens were examined with a stereomicroscope and SEM. Surface roughness and morphology of the CAD/CAM restorative materials were characterized after treatment. Data were analyzed using ANOVA and Tukey's test. Results: The surface treatment, type of CAD/CAM restorative material, and water storage periods showed a significant effect on the μTBS (p 0.001). For the LU/BF system, there was no significant difference in the bond strength values between different surface treatments (p > 0.05). On the other hand, for the VE/BF system, surface treatment with HF + S showed higher bond strength values compared with SB and HF surface treatments (p 0.05). Surface roughness and SEM analyses showed that the surface topography of CAD/CAM restorative materials was modified after treatments. Conclusion: The effect of surface treatments on the bond strength of novel CAD/CAM restorative materials to resin cement is material dependent. The VE/BF CAD/CAM material provided higher bond strength values compared with the LU/BF CAD/CAM material. Keywords: adhesion, microtensile, polymer-infiltrated ceramic network, resin cement, resin nanoceramic, surface roughness, surface treatments