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Although the effectiveness of methotrexate (MTX) in the treatment of psoriasis is very well established, the mechanism of action is poorly understood. It was suggested that the therapeutic effect of MTX in psoriasis might be mediated by inhibition of adhesion molecule expression. The aim of our study was to investigate the different effects of MTX treatment on cell proliferation, inflammatory infiltrate, adhesion molecules, and angiogenesis in psoriasis, and to clarify the mechanism by which MTX exerts its therapeutic effects. Clinical response, the morpho-phenotypic changes, epidermal thickness, and mitosis count were analyzed and the expression of CD31 and ICAM-3, proliferative markers such as Ki-67, PCNA, were evaluated by immunohistochemical techniques in lesional psoriatic epidermis, before and after the treatment with MTX in ten patients. In posttreatment biopsies a decrease in the degree of epidermal hyperplasia and a significant reduction in the severity of the inflammatory infiltrate (P<0.05) were observed. In addition, CD31 and ICAM-3 expression was significantly decreased on dermal cellular infiltrate, (respectively; P<0.05, P<0.01). Ki67 and PCNA expression were suppressed concurrently in about 90% of cases (P<0.01). We suggest that MTX may have an inhibitory effect on an initial integral component of the pathways that lead to psoriasis. Immunopharmacologic intervention in adhesion event has the potential to improve psoriasis. Inhibition of revascularization may be another mechanism of action of MTX.