Elevated levels of proinflammatory cytokines, including tumor necrosis factor-alpha, are found in skin lesions and plasma of patients with psoriasis. Clinical improvement of psoriasis with cyclosporin A treatment is accompanied by downmodulation of proinflammatory epidermal cytokines. In this study to determine the effects of cyclosporin A on the ultrastructural changes and tumor necrosis factor-alpha and intercellular adhesion molecule-1 expression in psoriasis, biopsy specimens before and after cyclosporin A treatment were evaluated ultrastructurally and immunohistochemically. Ten patients were given 3-7.5 mg/kg oral cyclosporin A for 6 months. Before and after treatment full thickness of 4-mm punch biopsies were obtained from patients and from 6 healthy volunteers. Samples were processed for electron microscopic and immunohistochemical evaluation. The treatment was well tolerated with complete clinical improvement. The ultrastructural changes such as reduction of tonofilaments, dilatation of intercellular space, and interruption in lamina densa were recovered by cyclosporin A treatment. The increased staining intensity of tumor necrosis factor-alpha and intercellular adhesion molecule-1 on epidermal keratinocytes and endothelial cells was reduced after cyclosporin A therapy. Cyclosporin A treatment results in total normalization of the electron microscopic picture of psoriasis and its beneficial effect depends on the direct inhibition of tumor necrosis factor-alpha and consequently intercellular adhesion molecule-1.