FK 506 is a new immunosuppressive agent with a similar molecular action to cyclosporin A. We have investigated immunohistochemical changes in lesional biopsies of seven patients with severe recalcitrant chronic plaque psoriasis receiving systemic FK 506 therapy. Within 4 weeks of start of treatment, there was a striking reduction in psoriasis area and severity index (mean reduction 87.4%), accompanied by marked reductions in dermal and epidermal CD4+and CD8+cells. Investigation of biopsies obtained 4–8 weeks after start of treatment revealed a significant fall in the numbers of activated mononuclear cells expressing CD25 (IL-2 receptorα-chain), HLA-DR, or CDlla (lymphocyte function-associated antigen-1, LFA-lαchain). In contrast, the number of epidermal CD1+(Langerhans) cells increased in response to FK 506 therapy. Study of leukocyte adhesion-related epitopes in active disease revealed strong expression of CD54 (intercellular adhesion molecule-1, ICAM-1) and E-selectin (previously known as endothelial leukocyte adhesion molecule-1) both on microvascular endothelial cells and of ICAM-1 on infiltrating mononuclear cells; ICAM-1 was also expressed weakly on epidermal keratinocytes. Vascular cell adhesion molecule-1 (VCAM-1) was either absent or expressed rarely on vascular endothelium. In response to FK 506 treatment, both ICAM-1 and E-selectin expression on blood vessels was reduced consistently but nevertheless persisted, even in individuals exhibiting total clearance of psoriatic lesions. The results are consistent with interference by FK 506 with production of pro-inflammatory cytokines, autocrine growth factors and the expression of adhesion molecules which are thought to regulate key interactions between keratinocytes, leukocytes and vascular endothelial cells in the pathogenesis of psoriasis.