The distribution of epidermal Ca-binding protein was examined in rat tissues using immunodiffusion and immunofluorescence techniques to investigate its possible physiological role. Epidermal Ca-binding protein was demonstrated in the basal proliferative cell layer of all Malpighian epithelial and related tissues (epidermis, sebaceous glands, cornea, esophagus and vagina) as well as in ependyma of brain and in the epithelia of the lens. No immunoreactivity for epidermal Ca-binding protein was found in other tissues including dermis, muscle, cartilage, blood vessels, nerve tissue, liver, endocrine glands, urogenital tract and intestinal and respiratory epithelium. the presence of a protein immunologically indistinguishable from epidermal Ca-binding protein in proliferative cells suggests that it may be involved in the control of Ca-dependent processes perhaps related to mechanical damage and continued proliferation.