Objective: To evaluate the clinical performance of posterior resin composite restorations regarding experimental and regular adhesive protocols in caries affected-dentin (CAD). Material and methods: A total of 92 class I and class II cavities with carious lesions were selected and randomly assigned to the following groups: (1) bioactive glass-ceramic powder/two-step etch and rinse system, (2) control/two-step etch and rinse system, (3) bioactive glass-ceramic powder/two-step self-etching system, and (4) control/two-step self-etching system. Two operators carried out the adhesive protocols and restored the cavities with a nano-hybrid resin composite. Participants were followed up at 1 week and 6, 12, and 18 months for clinical evaluation performed by two blinded examiners and calibrated according to FDI criteria. Data were analyzed using Kruskal-Wallis and Dunn tests with a confidence of 95%. Results: The clinical performance of resin composite restoration was not affected by the experimental use of an adhesive protocol including a bioactive glass-ceramic powder for 18 months post-procedure. However, there was a significant difference between group 2 and group 4 (p < 0.05) for marginal adaptation (18 months). Group 2 was significantly different from group 3 (p < 0.05) for fracture of material/retention (18 months) and marginal adaptation (1 week); group 2 showed a better performance. Conclusion: Adhesive protocols can alter the clinical performance of posterior restorations in terms of marginal adaptation and the fracture of material/retention in CAD. Clinical significance: Adhesive protocols may influence the success of resin composite restorations in CAD; this is important because failure can lead to caries, re-incidence, and/or clinical re-work.