The case histories of three patients with generalized mastocytosis are presented and discussed. The first patient had extensive urticaria pigmentosa, hepatosplenomegaly, polylymphadenopathy and myelofibrosis. The best therapeutic results were obtained with prednisone in combination with an antihistamine. The second patient showed virtually no skin lesions but had splenomegaly and upper abdominal pains. The latter disappeared after splenectomy. The spleen disclosed a greatly increased histamine concentration. The third patient started with thrombocytopenic purpura that was cured by splenectomy. Seven years later, urticaria pigmentosa developed with mast cell proliferation in skin and bone marrow and a low IgM level. In addition to skin biopsies, determination of histamine in blood and urine can supply valuable diagnostic information, especially in the more advanced cases. In systemic mastocytosis immune deficiency may occur.