Objectives: To evaluate the effect of gamma irradiation of enamel and dentin on the micro-tensile bond strength of the resin composite with two adhesive systems and glass ionomer restorative materials. Moreover, the effect of a casein phosphopeptides-amorphous calcium phosphate desensitizing agent application after irradiation and before restoration on the micro-tensile bond strength of the same restorations was evaluated.Methods: A total of 15 extracted molars were prepared to obtain 90 enamel and dentin samples. The samples were divided into 3 main divisions (30 samples each) according to the restorative material and type of adhesive system used. Each division was divided into 3 groups (10 samples each). One group served as a control, the 2nd one was subjected to irradiation and the 3rd one was subjected to irradiation followed by the application of the CPP-ACP desensitizing agent (MI Paste Plus). Finally each group was divided to two subgroups (5 samples each); one for enamel and the other for dentin. While being immersed in saline solution the specimens were irradiated with the same dose of 60 Gy fractionated over 4 days (15 Gy/day). The CPP-ACP desensitizing agent was applied on the occlusal surface of the specimens and left in contact with the specimens for 30 minutes on a daily basis for 1 week. After each treatment with the desensitizing agent, the specimens were stored in artificial saliva that was renewed daily until the restorative step.A nano-filled resin composite restorative material was used (Filtek Z350 XT Universal Restorative) with two types of adhesive systems; a total-etch adhesive system (Adper Single Bond 2 preceded by acid-etching of the tooth surfaces using Scotchbond etchant) and a more recent self-etch adhesive system (Single Bond Universal). The restoration with the glass ionomer restorative material (Equia Fil) was also preceded by conditioning of the tooth specimen surfaces using a polyacrylic acid conditioner. The specimens were restored with the different restorations according to the manufacturer’s instructions to obtain restoration blocks of 3-4mm height. Each block was sectioned to produce a series of beam-shaped samples (2-3 samples for enamel and 4-5 samples for dentin) with cross-sectional area of 0.8-1.0mm2 and length of 6-8 mm. Each sample was attached with its ends to a specially designed attachment jig and the whole assembly was mounted on the universal testing machine for the measurement of the micro-tensile bond strength (µ-TBS). The failed specimens were then examined using a USB digital microscope to determine their failure modes.Results: The results of the enamel substrate groups bonded with the resin composite using the total-etch adhesive system revealed that the control group showed the highest significant mean µ-TBS value followed by the irradiated group, while the irradiated and desensitized group possessed the lowest significant mean µ-TBS value. Within the enamel substrate groups bonded with the resin composite using the self-etch adhesive system, the control group showed the highest significant mean µ-TBS value followed by the irradiated group, while the irradiated and desensitized group possessed the lowest significant mean µ-TBS value. Among the enamel substrate groups restored with the glass ionomer restorative material, the irradiated and desensitized group possessed the highest significant mean µ-TBS value with no significant difference between the control group and the irradiated group. The results of the dentin substrate groups bonded with the resin composite using the total-etch adhesive system showed that the irradiated and desensitized group possessed the lowest significant mean μ-TBS value with no significant difference between the control and the irradiated groups. On the other hand, the dentin substrate groups bonded with the resin composite using the self-etch adhesive system revealed that the irradiated and desensitized group possessed the lowest significant mean μ-TBS value with no significant difference between the control group and the irradiated group. The results of the dentin substrate groups restored with the glass ionomer restorative material revealed that the irradiated and desensitized group possessed the highest significant mean µ-TBS value with no significant difference between the control group and the irradiated group. The control and irradiated enamel substrate groups bonded with the glass ionomer restorative material recorded significantly lower mean μ-TBS values than the control and irradiated enamel substrate groups bonded with the resin composite restorative material using the total-etch or the self-etch adhesive systems, while the irradiated and desensitized enamel groups bonded with the glass ionomer restorative materials showed similar mean μ-TBS value to those of the resin composite using the total-etch or the self-etch adhesive systems. Interestingly, the control and irradiated dentin substrate groups bonded with the glass ionomer restorative material recorded significantly lower mean μ-TBS values than the control and irradiated dentin substrate groups bonded with the resin composite restorative material using the total-etch or the self-etch adhesive systems, meanwhile the irradiated and desensitized enamel groups bonded with the glass ionomer restorative materials possessed higher mean μ-TBS value than those of the resin composite using the total-etch or the self-etch adhesive systems. Furthermore, there were no significant differences when comparing the mean µ-TBS values of all enamel and dentin substrate groups (control, irradiated, irradiated and desensitized) whether bonded with resin composite restoration using total-etch or self-etch adhesive systems, or glass ionomer restoration except for the irradiated substrate groups bonded with the resin composite using the self-etch adhesive system where the dentin group showed a significantly higher mean µ-TBS than the enamel group, and the control substrate groups restored with the glass ionomer restorative material where the dentin group showed significantly higher mean µ-TBS value than the enamel group. Evaluation of the failure modes after µ-TBS testing indicated that adhesive and mixed failure modes were observed for the groups of the low µ-TBS values. Meanwhile cohesive and mixed failure modes were frequently seen in the groups that possessed higher µ-TBS values.Conclusions: Gamma irradiation of enamel has a detrimental effect on the bond strength of resin composites regardless of the type of adhesive system used. Gamma irradiation of enamel and dentin has no significant effect on the bond strength of glass ionomer restorative material. In general, resin composite restorative materials have higher bond strengths than glass ionomers when bonded to non-irradiated and non-desensitized tooth substrates as well as irradiated tooth substrates. New formulations of the self-etch adhesive systems may exhibit bond strengths similar to that of the total-etch adhesive systems. The CPP-ACP desensitizing agent lowers the bond strength of the resin composite material to the tooth structure but enhances that of the glass ionomer material.