Elastic fibers are essential extracellular matrix macromolecules comprising an elastin core surrounded by fibrillin-rich microfibrils. Fibulin-5, a microfibril, has been identified as one of the secreted extracellular matrix proteins that shows function as a scaffold for elastic fibers. However, the distribution of fibulin-5 in the skin is not clear. We report a case of a 43-year-old woman with erythema and subsequent wrinkling that met the clinical and histological criteria for mid-dermal elastolysis. We investigate the mechanism by which this disease occurs. The distribution of elastin, CD68, matrix metalloproteinase (MMP)-9, and fibulin-5 was examined immunohistochemically from both erythematous and wrinkled skin. There were numerous CD68+ and MMP-9-producing histiocytes and giant cells in the erythematous lesions. Faint fibrillar staining of fibulin-5 was found in the deep dermis. In the wrinkled skin, there were few CD68+ histiocytes or giant cells. Elastin immunoreactivity disappeared from the mid-dermis. Fibulin-5 colocalized in the lower dermis, shorter than in the erythema. Mid-dermal elastolysis may be initiated by MMP-9 produced by histiocytes and giant cells through its degradation of elastic fibers. In the lower dermis of the wrinkled skin, the fragmented expression of fibulin-5 was associated with the incomplete reproduction of the elastic fibers.