The phenotypical heterogeneity of human liver macrophages was analyzed with monoclonal antibodies that recognize antigens specific for the monocytemacrophage lineage. Most liver macrophages in normal and diseased liver were positive for CD68, whereas fewer matured macrophages were detected by 25-F9. Comparative staining of mirror sections revealed some to be doubly positive and others to be singly CD68 positive. Quantitative analysis confirmed the difference, suggesting heterogeneity of maturation in liver macrophages. Most liver macrophages in the normal liver were negative for CD14, a receptor for lipopolysaccharide and lipopolysaccharide-binding protein complexes. Liver macrophages in liver diseases were activated to express CD14 at varying degrees and were involved in the clearance of lipopolysaccharidelipopolysaccharide-binding protein complexes. FcyRI, a receptor for monomeric IgG that is involved in antibody-mediated cell cytotoxicity, was negative in the normal liver, but was expressed in liver macrophages at inflammatory sites (e.g., in piecemeal and focal necrosis) in diseased livers. FcyRII was expressed in most liver macrophages, as well as in sinusoidal endothelial cells; FcyRIII was expressed in a smaller number of liver macrophages. Expression of FcyRII and FcyRIII was increased in chronic active hepatitis. These results suggest that liver macrophages are heterogeneous in maturation and function and that they are activated in liver diseases as shown by the novel expression of CD14 and FcyRI. The restricted expression of FcyM indicates that FcyRI-positive macrophages, in cooperation with cytotoxic T lymphocytes, may play an important role in liver cell injury through antibody-mediated cell cytotoxicity.