Computer-aided design/computer-aided manufacturing (CAD/ CAM) systems have been widely used in dentistry [1][2][3] since the first dental CAD/CAM restoration was reported in the 1980s [4,5]. CAD/ CAM resin composites consist of a matrix resin and inorganic fillers treated with a silane coupling agent [6][7][8]. The matrix resin forms the basis of the composite structure and is composed of organized methacrylate-derived polymers, such as urethane dimethacrylate (UDMA), bisphenol A-glycidyl methacrylate, or triethylene glycol dimethacrylate (TEGDMA) [7]. Inorganic fillers, which are commonly made of silica, zirconia, and alumina, can be used to reinforce the composite structure because of their excellent mechanical properties [9][10][11]. For CAD/CAM resin composites, 0.1 μm or smaller nanofillers composed of chemically stable inorganic materials are often used to improve the mechanical properties and provide polishabil-ity to create a smooth surface [12][13][14][15][16]. Because inorganic fillers are chemically stable, surface modification using silane coupling agents is required to adhere the fillers to the organic matrix resin [17][18][19]. γ-Methacryloyloxypropyl trimethoxysilane (γ-MPTS) is a typical silane coupling agent, and it forms a 1.9-3.0-nm-thick layer between fillers and the matrix resin [20,21].Water ingress leads to hydrolytic breakdown of the bonds between the silane and filler particles [22,23]. This water-induced degradation negatively affects the restoration longevity and mechanical properties [6,[22][23][24][25]. While degradation of silane coupling layers has been qualitatively reported, the quantitative details have not been revealed because arbitrary control of the silane coupling ratio of the filler is not possible with conventional in vitro tests.Rigorous mathematical theories of homogenization have been proposed for quantitative analysis of composite materials [26][27][28]. These theories assume that the material properties are periodic functions of the micro-scale variables, where the period is very small compared with the macro-scale variables. With this assumption, the equivalent macro-scale material properties can be calculated from known or arbitrary micro-scale properties. In dentistry, in silico homogenization analysis has been used to investigate multi-factorial J Prosthodont Res. 2021; **(**):