Fresh and cultured human Langerhans cells display disparate functional programs, based on their capacities to activate autologous and allogeneic T cells and with respect to their susceptibility to inhibition by transforming growth factor-beta (TGFβ). We have compared the functional properties of epidermal antigen-presenting cells (APC) procured from uninvolved and involved skin of patients with psoriasis with fresh and cultured normal epidermal cells. Freshly obtained psoriatic epidermal APC resembled cultured normal epidermal cells in their superior capacity to activate syngeneic and allogeneic T cells; fresh normal epidermal cells failed to activate syngeneic T cells and induced only modest proliferation among allogeneic T cells. The modest T-cell–activating properties of fresh, normal epidermal cells were not sup- pressed by TGFβ, whereas the T-cell–activating potential of psoriatic epidermal cells, cultured normal epidermal cells and blood APC was inhibited approximately 50% by TGFβ. Thus, fresh psoriatic epidermal APC resemble cultured normal epidermal cells functionally. Because these properties are already evident in cells obtained from uninvolved psoriatic skin, the “cultured” functional phenotype of epidermal APC in this disease may precede the appearance of active psoriatic skin lesions. Surface marker analysis of normal and psoriatic epidermal cell suspensions revealed that virtually all of the bone marrow-derived cells in normal epidermal cell suspensions were conventional (CD 1⁺) Langerhans cells, whereas CD 1⁺ cells comprised only a minority of bone marrow—derived (CD45⁺) cells in psoriatic epidermis. It is speculated that some of the CD1^-, CD45⁺ cells in psoriatic epidermis may be Langerhans cells that have lost their “fresh” phenotype. These data indicate that an abnormality in epidermal APC function exists in psoriatic skin—even before clinical lesions develop, and we speculate that the abnormal capacity of psoriatic epidermal APC to activate syngeneic T cells may be important in the expression of keratinocyte pathology. Because psoriatic epidermal APC functions were profoundly inhibited in vitro by treatment with cyclosporin A, the effectiveness of this drug in psoriasis may be due in part to its ability to inhibit epidermal antigen-presenting cell function in vivo.