Purpose: The aim of this prospective randomized controlled clinical trial was to evaluate the 2-year clinical performance of a self-adhesive resin cement, RelyX Unicem (3M ESPE), used for cementation of ceramic inlays. In addition, the influence of selectively acid etching enamel prior to luting on marginal integrity, inlay integrity, tooth integrity, sensitivity, and complications of the restored teeth was assessed. The hypothesis tested was that there was no significant difference in these criteria between restorations with (Etch) or without prior enamel acid etching (Non-etch). Materials and Methods: Sixty-two IPS Empress 2 inlays/onlays were placed in 31 patients by two experienced clinicians. The restorations were luted with RelyX Unicem with (=experimental group; Etch) or without (=control group; Non-etch) prior enamel etching with phosphoric acid. At baseline, 6 months, 1 year and 2 years after placement, the restorations were assessed by two calibrated investigators using modified USPHS criteria. Results: The recall rate at 24 months was 96.6%. Two restorations were clinically unacceptable due to loss of retention, leading to a survival rate of 96.6% (Kaplan-Meier). No significant difference was noted between the experimental group and the control group regarding marginal integrity, inlay integrity, tooth integrity, complications and sensitivity (McNemar, p > 0.05). An obvious deterioration in marginal adaptation was observed after 24 months as only 21.7% (Etch = 23.4%; Non-etch = 20%) of the restorations exhibited an excellent marginal adaptation compared to 70.7% (Etch = 75%; Non-etch = 66.7%) at baseline. In 74.9% of the restorations, small, still clinically acceptable marginal deficiencies were observed (Etch = 76.6%; Non-etch = 73.2%). Conclusion: The self-adhesive resin cement RelyX Unicem showed acceptable clinical behavior after two years of clinical service. Selective enamel etching prior to luting had no significant influence on marginal integrity, inlay integrity, tooth integrity, sensitivity or complications of the restored teeth after 24 months. Longer term evaluation is needed to confirm this finding. Keywords: glass ceramics, adhesive inlays, luting composite, self-adhesive, clinical trial