Recent data suggest that imbalances in production and secretion of cytokines, in particular interferon-gamma (IFN-gamma), may be crucial in the pathogenesis of psoriasis. In order to exert its role on target cells, IFN-gamma has to interact with a specific cell membrane receptor termed the IFN-gamma-receptor (IFN-gamma R). We studied the distribution of IFN-gamma Rs in frozen skin biopsies from 25 psoriatics and 5 normal controls with two unrelated monoclonal antibodies, and compared its distribution with that of the IFN-gamma-inducible HLADR- and ICAM-1 antigens. In normal skin, IFN-gamma Rs were restricted to the basal cell layer; weak staining was found on scattered mononuclear cells in the papillary dermis. In 13/25 active psoriatic lesions, additional suprabasal immunoreactive foci, and in 5/25 cases, diffuse immunoreactivity of the entire epidermis were seen. No striking topographical similarities between the site and number of IFN-gamma R+, HLADR+ and ICAM-1+ keratinocyte foci were observed, suggesting that cytokines other than IFN-gamma induce HLADR-antigens on psoriatic keratinocytes in vivo. The restricted distribution of IFN-gamma R on the germinative cell layer in normal skin confirms the role played by IFN-gamma in the normal growth regulation of the epidermis. The de novo suprabasal expression of IFN-gamma R in psoriasis argues against the current hypothesis that IFN-gamma R are down-regulated due to a local excess of IFN-gamma or transforming growth factor alpha (TGF-alpha). Whether IFN-gamma Rs in psoriatic skin are functionally normal and involved in signal transmission, remains to be studied.