The purpose of the present study was to (1) investigate the micro-shear bond strength and failure mode of a novel methacryloxydecyl-dihydrogen-phosphate (MDP) calcium-fluoride–releasing self-adhesive resin cement (TheraCem, BISCO) to a tooth structure (enamel and dentin) and to yttrium-stabilized zirconia after thermocycling, and to (2) compare the results with a universal non–MDP-containing self-adhesive resin cement (RelyX Unicem, 3M ESPE) as a control. Enamel and dentin specimens (20 discs each) were obtained by using a diamond saw (IsoMet 4000, Buehler) with copious water coolant. Twenty zirconia plates were obtained from IPS e.max ZirCAD blocks (Ivoclar Vivadent) and sintered in an inFire HTC speed hightemperature furnace (Dentsply Sirona). Resin-cement micro-cylinders were created on the bonded surface and filled with the tested cements (n = 10 for each surface/ cement combination): Group A (control) used non–MDP-containing RelyX, while group B (tested cement) used MDP-containing TheraCem MDP. Cements were left to self-cure for 5 minutes. All specimens were thermocycled for 5,000 cycles (THE- 1100, SD Mechatronik). Micro-shear bond strength was measured using a universal testing machine, and debonded surfaces were examined for failure mode analysis with all morphologic and ultrastructure changes using a scanning electron microscope (Quanta 250 Field Emission Gun, FEI) attached with an energy dispersive x-ray (EDX) unit. The results were statistically analyzed. TheraCem had a slightly higher micro-shear bond strength (MPa) value than RelyX. Within enamel, TheraCem (6.46 ± 1.37 MPa) had a significantly higher mean μ-SBS value than RelyX (3.04 ± 0.99 MPa) (P = .002). Similarly, TheraCem in dentin (10.67 ± 1.27 MPa) had a significantly higher mean value than RelyX (6.46 ± 1.74 MPa) (P = .014). As for zirconia, TheraCem (39.76 ± 1.18 MPa) had a significantly higher mean μ-SBS value than RelyX (27.04 ± 1.92 MPa) (P .001). Using MDP-containing calcium-fluoride–releasing self-adhesive resin cement (TheraCem) may improve bond strength to all tested substrates (enamel, dentin, and zirconia) and can be considered a promising cement for many clinicians. Further clinical studies are required to provide long-term clinical success data.