Chitosan-silica xerogel hybrid membranes were fabricated using a sol-gel process and their potential applications in guided bone regeneration (GBR) were investigated in terms of their in vitro cellular activity and in vivo bone regeneration ability. TEM observation revealed that the silica xerogel was dispersed in the chitosan matrix on the nanoscale. The hybrid membrane showed superior mechanical properties to chitosan in the wet state and the rapid induction of calcium phosphate minerals in simulated body fluid, reflecting its excellent in vitro bone bioactivity. Osteoblastic cells were observed to adhere well and grow actively on the hybrid membrane to a level higher than that observed on the chitosan membrane. The alkaline phosphatase activity of the cells was also much higher on the hybrid than on the chitosan membrane. The in vivo study in a rat calvarial model demonstrated significantly enhanced bone regeneration using the hybrid membrane compared to that observed using the pure chitosan one. Histomorphometric analysis performed 3 weeks after implantation revealed a fully closed defect in the hybrid membrane, whereas there was only 57% defect closure in the chitosan membrane.