Kaposi's sarcoma (KS) follows a different clinical course in Mediterranean and immunodeficiency related cases and has a poorer prognosis in the latter. We investigated 40 patients with Mediterranean and eight with immunodeficiency related KS by histomorphology and immunohistology in comparision to the clinical presentation in order to identify characteristic patterns distinctive for each of these KS forms. We also evaluated oncoprotein activation and phosphotyrosine activity. Tissue sections were stained with hematoxylin-eosin (H&E), Mallory's phosphotungstick acid hematoxylin (PTAH), Hotchkiss-McManus' periodic acid - Schiff reaction (PAS), Masson's trichrome, Pinkus' orcein-Giemsa, Lapham's method for myelin, Bielschowski-Gomori's silver impregnation for reticular fibres, Bodian's silver impregnation for neurofibrils, and Wartin-Starry silver impregnation for fungi and bacteria. Immunohistochemistry was performed on deparaffinated sections using the microwave technique with avidin-peroxidase and 3-amino-ethyl-carbazole for alpha smooth muscle actin, CD34, phosphotyrosine, p53, and bcl-2. Mediterranean KS was characterized by pseudocapsule formation around nodules, which has been lost in immunodeficiency related KS. The latter, additionally, showed outstanding infiltrative growth with lace-like involvement of subcutaneous fat, colonization of perineuronal-periadnexal adventitial dermis, irregular vascular lacunae encircling vessels and/or adnexa, collections of histiocytoid-like cells, intravascular papillary projections of atypical endothelia cells. Both types could further be characterized by presence of alpha smooth muscle actin and CD34 expressing cells, high levels of phosphotyrosinase in plump spindle cells and variable expression of p53, sometimes coexpressed with phosphotyrosinase indicating cellular activation. The oncoprotein bcl-2 was not detected in this tumor material. The particular clinical features of Mediterranean and immunodeficiency related forms of KS may be reflected, at least in part, in characteristic histomorphological findings.