A killing process is described where macrophages destroy 3H Thymidine prelabeled Leishmania parasites during the process of phagocytosis. This phagocytosis associated killing may represent a first line of defense and reduces drastically the amount of parasites homing in the macrophages. Treatment of the macrophages with anti-TNF antibody inhibited the phagocytosis associated killing. Soluble TNF had no effect on Leishmania parasites. Macrophages performed the killing process in the complete absence of any secreted TNF. Experiments using fixed macrophages and macrophage membranes revealed the existence of a 26 Kd membrane-TNF molecule. This membrane TNF was active against a TNF sensitive tumor cell line whereas the fixed cells or the isolated membranes had no cytotoxic effect on Leishmania parasites. This data indicates, that the Leishmanicidal effect was mediated through TNF but that apparently TNF itself was not the cytotoxic principle. Experiments using organ macrophages from Leishmania infected susceptible C 57/Bl 6 healer mice demonstrated that during the first 4 weeks of the infection the organ macrophages were totally unable to destroy Leishmania parasites independent of additional activation whereas the mechanism to destroy P815 tumor cells was unaffected. Similar data were obtained in therapy protocols using interferon gamma encapsulated in liposomes in order to target the substance to the macrophages. Also under these in vivo conditions the organ macrophages could not be activated and no beneficial effect was obtained by this activation treatment. In contrast, when therapy was started early (day 0 or 1) or late (5 weeks) after infection a highly significant reduction of the parasite burden was obtained.(ABSTRACT TRUNCATED AT 250 WORDS)