Macrophage-mediated cytotoxicity toward tumor cells usually involves extracellular lysis of the targets. In this study, we report that liver macrophages from rats treated with lipopolysaccharide (5 mg/kg, intravenous) also kill certain tumor cell targets by phagocytosis. Liver macrophages were coincubated with P815 mouse mastocytoma cells for 24 to 72 hr at an effectorbarget ratio of 10 : 1. Macrophage phagocytosis was characterized by flow cytometry and by light and electron microscopy. For flow-cytometric studies, P815 cells were prelabeled with the fluorescent dye 1,l'dioctadecyl -3,3,3', 3'tetramethylindocarbocyanine perchlorate. We found that coincubation of macrophages with labeled targets resulted in a timedependent increase in macrophage-associated fluorescence, reaching a maximum at 72 hr. This correlated with light-microscopic observations of increased numbers of tumor cells in the macrophages and enhanced macrophage surface area and density. Electron microscopic studies revealed that the initial event in the phagocytic process involved the capture of P815 cells by the pseudopodia of the macrophages. Target cells were then surrounded by lamellipodia, internalized in phagosomes and destroyed. These data, together with previous studies, provide evidence for multiple mechanisms of cytotoxicity mediated by activated liver macrophages. (HEPATOLOGY 1991;14:3 18-324.) Destruction of tumor cells by macrophages is generally thought to occur by two distinct mechanisms: macrophage-mediated tumor cytotoxicity and antibodydependent cellular cytotoxicity (ADCC). Macrophagemediated tumor cytotoxicity is a relatively slow, contactdependent, nonphagocytic process (1). In the initial step, target cells bind to an activated macrophage. This is followed by active secretion of lytic effector molecules from the macrophages. ADCC involves lysis of antibodycoated targets, primarily through oxidative mechanisms (2). The reaction is dependent on the presence of Fc receptors on the macrophages and antibodies on the