The purpose of this study was to investigate histamine and skin mast cells in psoriasis before and during 6 months of treatment with high-dose ranitidine. Sixteen psoriasis patients, presenting a mean PASI score of 15.4, were compared with 13 age- and sex-matched healthy controls. Resting extracellular skin levels of histamine and histamine release to mast cell secretagogues, as measured by the microdialysis technique, were increased in involved psoriasis skin compared to normal skin in the controls. Plasma histamine, but not basophil histamine release, was significantly increased in the patients. Mast cells and lymphocytes were significantly increased in numbers in involved versus non-involved skin in the patients, the lymphocytes being predominantly T-lymphocytes expressing HLA-DR activation. During 6 months of ranitidine treatment, mean PASI score of 15.4 decreased to 5.8. The lymphocyte infiltration, but not mast cell numbers, was significantly reduced during treatment, and histamine release to mast cell secretagogues was normalized. These observations suggest that skin mast cells in active psoriasis are functionally hyperreactive. The biochemical findings together with the clinical effect of ranitidine indicate that histamine may be involved in the pathophysiology of psoriasis.