The hypothesis was tested that tissue necrosis in acute experimental amebic liver abscess in hamsters is not caused directly by the parasite but rather, indirectly, by the destruction of closely surrounding leukocytes that release their lysosomal enzymes and damage neighboring liver cells. Axenically grown trophozoites of Entamoeba histolytica strain HM-1 were injected intraportally into normal, hypocomplementemic, and leukopenic hamsters, and the lesions were studied histologically 2, 5, 10, and 24 hr after injection. Hypocomplementemia (less than 5% of normal CH50) and leukopenia (less than 1,000 leukocytes/ml) were achieved and sustained for up to 72 hr with repeated intraperitoneal injections of goat anti-hamster C3 and anti-hamster leukocyte antibodies, respectively. Decrease or absence of polymorphonuclear leukocytes in the vicinity of intrahepatic amebas effectively blocked deleterious effects of the parasites on surrounding hepatocytes. We conclude that in acute experimental amebic liver abscess the direct effect of the parasites on hepatocytes and their stroma is not responsible for tissue necrosis, but rather it is due to their indirect action through the destruction of inflammatory cells.