Summary Non-melanoma skin cancers are the most commonly diagnosed malignancies and are typically indolent in their clinical behavior. Although predisposing factors leading to the development of these cancers, such as ultraviolet irradiation, are well described, the molecular events involved in their pathogenesis are incompletely understood. The localization of bcl-2 expression within the skin was determined using immunohistochemical methodologies and an anti-bcl-2 monoclonal antibody. The cytoarchitectural distribution o f bcl-2 protein in normal skin included basal keratinocytes, the dermal papillae of the hair follicle, the keratinized Huxley's and Henle's layers, and the keratinized outer root sheath cells of the isthmus and in fundibulum o f the hair follicle. In addition, intense immunoreactivity was noted in the secretory coil of eccrine sweat glands. The distribution of bcl-2 protein within normal skin did not correlate with the known histologic localization of stem cell compartments. Basal cell carcinomas expressed high levels of bcl-2 protein. In contrast, squamous cell carcinomas typically exhibited no immunohistochemically detectable bcl-2 protein. The findings suggest a potential contribution of bcl-2 gene deregulation to the pathogenesis of some types of non-melanoma skin cancer.