Purpose: To compare the clinical performance of a glass hybrid restorative system, EQUIA Forte, with that of a nanohybrid resin composite, Tetric EvoCeram, in two-surface class II cavities. Materials and Methods: This multicenter, randomized controlled clinical study was conducted at four different dental schools. In total, 360 restorations were placed in patients in need of two class-II, two-surface restorations in the molar region of the same jaw. Each patient received one glass hybrid restoration (EQUIA Forte, GC) and one resin composite restoration (Tetric EvoCeram, Ivoclar Vivadent). Two independent evaluators performed a clinical evaluation of each site after 1 week (baseline), 1 year, and 2 years using the criteria of the FDI World Dental Federation (FDI-2). Results: The estimated survival rates at the 2-year recall were 93.6% and 94.5% for EQUIA Forte and Tetric EvoCeram, respectively. There were no significant differences in the survival rates or in any of the evaluated esthetic, functional or biological properties between EQUIA Forte and Tetric EvoCeram restorations (p ˃ 0.05). Conclusion: Both the glass-hybrid restorative system and nanohybrid resin composite showed good clinical performance in moderate to large two-surface class II restorations in a 2-year follow-up. Keywords: clinical trials, resin composite, glass-hybrid system, multicenter, split-mouth