Topical application of tumor-promoting agents to the dorsal skin of female SENCAR mice on a twice-weekly basis resulted in a reduction in density per unit area of bone marrow-derived Thy-1+ dendritic cells. Activity was observed for well-established tumor-promoting doses of promoting agents of several different chemical types, including 12-O-tetradecanoylphorbol-13-acetate (TPA, diterpene diester), anthralin (dihydroxyanthrone), and n-dodecane (n-alkane). A reduction in density of the same cells was also observed on the basis of the asialoGM1 lipid as a surface marker after TPA treatment. No parallel effect was observed for epidermal Langerhans (Ia+) cells, the second major epidermal immunofunctional cell type, except in the case of anthralin, a finding which is consistent with the reported toxicity of this agent. The stage 2 promoting agent mezerein was unique in inducing a consistent increase in Langerhans cell densities, but did not affect the density of Thy-1+ cells when applied for a prolonged period unless applied following four doses of TPA. In contrast to the SENCAR strain, the promotion-resistant Balb/c and C56BL/6 strains showed no response with respect to TPA-induced reduction of Thy-1+ cell density. In addition to effects on density, the above tumor-promoting agents induced morphological changes in both Thy-1+ and Langerhans cells. When these changes were placed on a quantitative basis by the calculation of shape and area fraction parameters, marked and significant effects were observed for the above agents, but not for the partial promoting agent mezerein nor the non-promoting phorbol diester 4-O-methyl-TPA. The effects of TPA were largely blocked by the potent anti-promoting agent fluocinolone acetonide, moreover. These findings further support an important role for quantitative and qualitative alterations in dendritic epidermal cells in tumor promotion.