Objectives: This study was carried out to evaluate clinically, at different time intervals, the marginal integrity of indirect resin composite restorations cemented by different cementation techniques for endodontically treated molars. Also an in-vitro study was performed to evaluate the marginal leakage of indirect resin composite restorations cemented by different cementation techniques in extracted endodontically-treated molars. Methods: As for the clinical study, sixteen patients received twenty resin composite indirect restorations cemented in maxillary and mandibular molars, ten of compound cavities and ten of complex cavities. Half of the restorations were cemented using conventional 2-steps etch & rinse resin cement and the other half with self-adhesive resin cement. Clinical performance was evaluated using modified USPHS criteria. Marginal integrity was judged on resin epoxy replicas, using Scanning Electron Microscope (SEM), while the tooth/restoration interface at the proximal gingival margin was evaluated using radiodensitometric analysis. As for the in-vitro study, twenty resin composite indirect restorations were cemented in twenty endodontically prepared mandibular molars, ten of standardized occluso-distal cavities with gingival seat prepared 1mm below cement-enamel junction (five cemented by self-adhesive resin cement while the other five restorations were cemented by conventional 2-step etch&rinse resin cement) and ten of standardized mesio-occlusso-distal (MOD) cavities with distal gingival seat prepared 1mm below the cement-enamel junction while the mesial gingival seat prepared 1mm above the cement-enamel junction (five cemented by self-adhesive resin cement while the other five restorations were cemented by conventional 2-step etch&rinse resin cement). After cyclic loading (360,000 cycles, with a force 50 N), the teeth were immersed in 2% methylene blue dye for 24 hours. Finally the teeth were sectioned twice and depth of dye penetration was measured (in mm) under a light stereomicroscope. Results: Clinical performance showed that there was no statistically significant difference between the two cementation techniques and between the two types of cavities. SEM evaluation showed that self-adhesive cementation technique had statistically significant lower means marginal perfection percentage than etch&rinse cementation technique. Compound cavity showed statistically significant higher mean marginal perfection percentage than complex cavity. The statistically significant lowest mean marginal perfection percentage was found with self–adhesive cementation technique in complex cavity after 18 months. Self-adhesive cementation technique showed higher means marginal gap width than etch&rinse cementation technique but the results was not significant. There was no statistically significant difference between means of marginal gap of the two cavity designs. There is a direct proportional relation between time and increase marginal gap width throughout the study. As for the radiodensity evaluation, there was a significant decrease in radiodensity for both cementation techniques in comparison to the baseline values of each throughout the study. Etch&rinse cementation technique showed higher decrease in radiodensity than self-adhesive resin cement starting from 6 months of clinical service. As for the in-vitro study, results showed that on the mesial surface, distal surface, and occlusal surface self-adhesive cementation technique showed statistically significant higher mean dye penetration than etch&rinse cementation technique. Irrespective to the type of cavity and technique of cementation, the mean depth of dye penetration occlusally was statistically lower than mean depth of dye penetration mesially. On the contrary, there was no significant difference between the types of cavity preparations. Conclusions: According to modified USPHS parameters, the overall clinical performance of both resin cements is considered acceptable. Conventional resin cement has a superior performance compared to the self-adhesive resin cement concerning percentage of perfect margins, even on the laboratory scale via the use of detection dyes. According to radiodensitometric analysis, it is recommended to use self-adhesive resin cements to cement sub-gingivally located indirect restorations. Increasing the number of missing walls is considered a significant predictor of restoration performance. Micromorphological evaluation revealed difference not observed by macroscopic level of evaluation. Monitoring of indirect resin composite restorations cemented by self-adhesive resin cements should be started as early as six months. While those cemented with conventional etch&rinse resin cements could be started at twelve months.