βig-h3 is an extracellular matrix protein and its expression is highly induced by TGF-β and it has also been suggested to play important roles in skin wound healing. In this paper, we demonstrate that βig-h3 is present in the papillary layer of dermis and synthesized in the basal keratinocytes in vivo and its expression is induced by TGF-β in normal human keratinocytes (NHEK) and HaCaT cells. βig-h3 mediates not only adhesion and spreading of keratinocytes but also supports migration and proliferation. These activities are mediated through interacting with α3β1 integrin. Previously identified two α3β1 integrin-interacting motifs of βig-h3, EPDIM, and NKDIL, are responsible for these activities. The results suggest that βig-h3 may regulate keratinocyte functions in normal skin and potentially during wound-healing process.