The disappearance of melanocytes because of defective adhesion is one of the accepted theories to explain vitiligo. Tenascin-C is a large, extracellular matrix glycoprotein that is thought to inhibit adhesion of melanocytes to fibronectin. The current study aimed to evaluate the pattern of tenascin-C expression in vitiligenous skin compared with normal pigmented skin by means of immunohistochemistry. The study was carried out on skin biopsies from lesional and perilesional skin of 30 patients with vitiligo and on normal skin of 10 healthy volunteers. Several histopathologic changes were observed in vitiliginous skin such as keratinocyte vacuolization, a thickened basement membrane, and dermal inflammatory changes. Tenascin-C was expressed in keratinocytes of the basal epidermal layer of normal skin biopsies at a mild intensity but it did not stain the dermis, whereas vitiligenous skin showed tenascin-C expression in most cases (93.3% ), in the papillary dermis, epidermis, and in both. Diffuse epidermal expression of tenascin-C correlated with more loss of pigment and continuous staining of tenascin-C in the papillary dermis correlated with progressive forms of vitiligo. Intense tenascin-C expression was associated with a more progressive course of the disease assessed by the vitiligo disease activity score. From this study, tenascin-C is highly expressed in the dermis, epidermis, and both of vitiligo as a secondary event for the disease. Keratinocyte is a source of tenascin-C in vitiligo, and diffuse epidermal expression of tenascin-C may induce more loss of melanocytes and melanin pigment. Dermal expression of tenascin-C in the vitiligenous lesion may be linked to the disease more than epidermal expression, because this pattern is only seen in a vitiligenous lesion and it is completely absent in normal and perilesional skin.