Graphene-reinforced chitosan scaffolds have been extensively studied for several years as promising hard tissue replacements. However, the interfacial interactions between graphene and chitosan are strongly related to the solubility, processability, and mechanical properties of graphene-reinforced chitosan (G-C) composites. The functionalization of graphene is regarded as the most effective way to improve the above mentioned properties of the G-C composite. In this study, the interfacial interactions between chitosan and functionalized graphene sheets with carboxylization (COOH-), amination (NH2-), and hydroxylation (OH-) groups were systematically studied at the electronic level using the method of ab initio simulations based on quantum mechanics theory and the observations were compared with reported experimental results. The covalent linkages between COOH-modified graphene and the chitosan units were demonstrated and the combination of multi-functionalization on graphene could regulate the interfacial interactions between graphene and the chitosan. The interfacial interactions between chitosan and properly functionalized graphene are critical for the preparation of G-C-based composites for tissue engineering scaffolds and other applications. (C) 2015 Elsevier B.V. All rights reserved.