Skin biopsies from healthy human skin and non‐lesional skin from patients with psoriasis were cultured for 24h and stimulated with interleukin‐1β(IL‐1β) and interferon‐γ (IFN‐γ) in a skin organ culture model and the induction of the psoriasiform regenerative epidermal phenotype was analysed using immunostaining. In the presence of IL‐1β, the psoriasiform regenerative epidermal phenotype was clearly induced. This involved strong up‐regulation of the expression of keratin 16, keratin 17, and keratinocyte transglutaminase (TGk) in the suprabasal layers, strong up‐regulation and a shift of the expression of keratin 5 and integrin β₁from the basal to suprabasal keratinocytes, and induction of the expression of ICAM‐1 and HLA‐DR on basal keratinocytes. The effects of IL‐1β in the organ cultures of normal skin could be completely neutralized by anti‐IL‐1 polyclonal antibodies. The effects of IFN‐γ in healthy and non‐lesional psoriatic skin were qualitatively similar to those of IL‐1β. The IFN‐γ‐induced epidermal expression of keratin 17 and TGk could be completely blocked by culturing the biopsies in the presence of IL‐1ra or anti‐IL‐1 antibodies, while the induction of HLA‐DR and ICAM‐1 was not inhibited. The induction of the psoriasiform regenerative epidermal phenotype by IFN‐γ is partially mediated via endogenous epidermal IL‐1. Copyright © 1999 John Wiley & Sons, Ltd.