Purpose: To investigate the clinical behavior of two different resin-based restorative systems in Class II cavities in a controlled prospective split-mouth study over 10 years. Materials and Methods: Thirty patients received 68 resin composite restorations (Solobond M + Grandio: n = 36; Syntac + Tetric Ceram: n = 32) by one dentist in a private practice. 35% of cavities revealed no enamel at the bottom of the proximal box, 48% of cavities provided 0.5 mm of remaining proximal enamel. Restorations were examined according to modified USPHS criteria at baseline, after 6 months, and 1, 2, 4, 6, 8, and 10 years. Results: Twenty-nine out of 30 patients attended the 10-year recall. The overall success rate of all restorations was 96.9%. One Grandio restoration suffered marginal fracture with exposed dentin and one Tetric Ceram restoration failed due to cusp fracture. After 10 years, Grandio showed higher surface roughness (p = 0.03) and less color match (p = 0.024; Mann-Whitney U-test). Molar restorations performed worse than premolar fillings regarding marginal integrity (4 and 10 years), filling integrity (4, 8, and 10 years), and tooth integrity (4, 8, and 10 years). The main reasons for degradation of resin composites were chipping and cracks in molar restorations after 8 years. Beyond the 4-year recall, marginal staining increased (43% bravo for stained margins at four years, 52% at 8 years, and 71% at 10 years). Tooth integrity deteriorated significantly due to more enamel cracks and chipping over time (9% at baseline and 89% after 10 years (p0.05). Conclusions: Direct resin composite restorations performed satisfactorily over 10 years of clinical service. Keywords: resin composites, nanofillers, clinical trial, marginal integrity, etch and rinse