Hapten-induced contact hypersensitivity has been well-characterized in humans as well as in animal models. However, it is not clear whether or not protein Ag can directly sensitize epicutaneously and induce a primary immune response. We demonstrated in this study, for the first time, that through epicutaneous exposure protein Ag in the absence of adjuvant sensitizes animals and induces a predominant Th2-like response. Furthermore, mice receiving repeated protein Ag sustained elevated levels of specific IgE. This animal model can be used to investigate the molecular mechanism controlling the differential Th1/Th2 development in skin diseases.