This in vitro study compared the marginal adaptation of all-ceramic MOD-inlays luted to human molars with four self-adhesive resin cements. Thirty-two human third molars were randomly assigned to four test groups (n = 8 per group). MOD cavities were prepared with approximal finishing lines in dentin and enamel. All-ceramic Empress 2 inlays were luted with four self-adhesive cements (Clearfil SA, iCEM, Bifix SE, seT). Oral stress was simulated by 90 day storage in water as well as by thermal and mechanical loading (TCML, 1.2 × 106 × 50 N, 6,000× 5°/55°, 1.6 Hz). The marginal fit was evaluated by scanning electron microscopy (SEM) and dye penetration. Data were analyzed with the ANOVA/Tukey's test (α = 0.05). The SEM investigation of the gingival cement margins (cement–tooth interface) showed values of perfect margin [percent] (means ± SD) after simulated aging between 84 ± 9% and 95 ± 5% for enamel and 80 ± 9% and 92 ± 3% for dentin. In enamel, seT showed significantly higher marginal integrity than iCEM after water storage and TCML (post hoc; p = 0.011). Furthermore, the marginal adaptation of iCEM in enamel deteriorated by simulated aging (p = 0.014, ANOVA). Mean values of dye penetration (percentage of dye entry into dentin) at the investigated restorations margins ranged between 3% and 8% for enamel and 12% and 22% for dentin. Clearfil SA, iCEM, and seT showed lower dye penetration in enamel than in dentin (Clearfil SA: p = 0.013, iCEM: p = 0.044, seT: p = 0.003). The results suggest that the four self-adhesive luting agents investigated seem to successfully bond to dentin-restricted as well as to enamel-restricted cavities, predicting good clinical performance.