Not all keratinocytes in human and rat hair follicles express MHC class I antigens (MHC I). In the present study, we report the first immunohistological profile of classical and non-classical MHC I expression in the skin of adolescent C57 BL-6 mice during the induced hair cycle. MHC I immunoreactivity (H-2b, H-2Db) is absent in the matrix and inner root sheath of growing (= anagen) hair follicles, and the dermal papillae are H-2b negative during catagen and telogen. This lack of normal MHC I expression may serve to sequester potentially damaging autoantigens from immune recognition. In addition, we present the first evidence of non-classical MHC class I antigen expression in normal mammalian skin: during the entire hair cycle, the distal hair follicle shows strong Qa-2 immunoreactivity, which appears to be restricted to an epithelial follicle compartment densely populated by gamma-delta T cells with which Qa-2 molecules may interact as part of a primitive antibacterial defense system of the follicle. The murine hair cycle is an attractive model for dissecting the functional roles of H-2b and Qa-2 molecules in hair biology and in related tissue-interaction systems.