Adequate internal adaptation and marginal sealing of resin luting cements are of particular importance for the success of cemented ceramic inlays. The purpose of this study was to investigate the initial adaptation of different resin cements at the tooth-inlay restoration interface at enamel versus dentin surfaces. Thirty-two extracted human molars were allocated to four groups. One Class II cavity was prepared in each tooth. In each group, half of the cavities’ gingival floors were on enamel while the other halves were on cementum. Lava Ultimate CAD/CAM inlays were luted to the cavities using the following adhesive systems: RelyX Unicem, RelyX Ultimate, eCement, and Variolink Esthetic DC. After staining teeth with silver nitrate solution, marginal and internal gap volumes were determined using micro-CT images. Statistical analyses were conducted by independent t test and one-way ANOVA followed by post hoc Tukey test (p < 0.05). The internal and marginal gap volume values were the highest for Variolink Esthetic DC at the dentin surface (0.629 ± 0.363) and (2.519 ± 1.007), respectively, and the lowest for RelyX Unicem at the enamel surface (0.005 ± 0.004) and (0.009 ± 0.003), respectively. The internal and marginal adaptation on the enamel surface for RelyX Unicem and RelyX Ultimate resin cements were comparable to each other and to eCement but significantly better than Variolink Esthetic DC cement. Regardless of the adhesive resin system used, adaptation on enamel is superior to that on dentin surfaces.