We examined the frequency, distribution, and immunophenotype (S-100 protein, CD1) of epidermal Langerhans cells (LC) in the epidermis overlying primary melanoma, and dermal dendritic cells (DC) in the dermis deep to melanoma, and in adjacent normal skin. There is a substantial reduction in S-100+ LC and a lesser decline in CD1+ LC in the epidermis over melanoma. There is a simultaneous increase in the frequency of cells expressing these phenotypes in the dermis deep to tumor. Double-staining studies in progress show coexpression of S-100 and CD1 in most of these cells. The depletion of S-100+/CD1+ DC from the peritumoral epidermis is maximum in deeper (Clark level III-V) and thicker (> 0.76 mm) tumors. The reduction in total DC in peritumoral epidermis is, however, proportionally less than the reduction in S-100+/CD1+ DC owing to an increase in cells that are S-100-/CD1+. The proportion of S-100+/CD1+ dermal DC deep to tumor is similar to that in normal epidermis and dermis, suggesting that there is no increased migration of S-100-/CD1+ DC from tumor-associated epidermis to subjacent dermis. Non-dendritic leukocytes in the dermis deep to tumor were increased in frequency, maximally in the dermis deep to thinner and more superficial melanomas. Most such cells were T lymphocytes with helper/inducer cells predominating. The data presented show substantial alterations in the frequency, distribution, and phenotype of LC/DC as melanoma evolves, alterations that may be critical for development of effective tumor-directed immunity.