Objective The purpose of this clinical study was to evaluate the performance of two different adhesive resin cement systems in the cementation of inlay/onlay restorations produced from resin nanoceramic blocks using the CAD/CAM system. Materials and Methods A total of 70 inlay/onlay restorations made from Cerasmart (GC, Tokyo, Japan) resin nanoceramic blocks using CEREC Omnicam (Sirona Dental, Bensheim, Germany) were placed in 53 patients. The restorations were cemented with RelyX U200 Automix (3M ESPE, Seefeld, Germany) self-adhesive resin cement (RXU) after selective enamel etching or with G-CEM LinkForce (GC, Tokyo, Japan) adhesive resin cement (GCL) in combination with a universal adhesive (G-Premio Bond) in selective etch mode. At baseline and after 6, 12, and 18 months, restorations were examined by two calibrated clinicians according to modified USPHS criteria. The data were analyzed using Chi-square (chi(2)) test and Friedman test (p < 0.05). Results After 18 months, two teeth at RXU group were endodontically treated due to hypersensitivities. At GCL group, three restorations were lost due to debondings (2) and ceramic fracture (1). The survival rates of RXU (94.3%) and GCL group (91.4%) exhibited no statistically significant difference (p = 0.661). No significant differences were detected for surface texture, secondary caries, anatomic form, color match, marginal discoloration, marginal integrity, interproximal contacts, and patient satisfaction (p > 0.05). Conclusions The two resin cement systems showed acceptable clinical performance for the cementation of resin nanoceramic CEREC Omnicam inlay/onlay restorations. Clinical Significance Resin nanoceramic restorations fabricated using CEREC Omnicam and cemented with either a self-adhesive or a universal adhesive/resin cement system demonstrated clinically acceptable results for posterior teeth in a single visit.