The purpose of this study was to determine if the SV40-transformed murine macrophage cell line IC-21 is a suitable model to study the selective high avidity binding of tumor cells by subpopulations of activated macrophages. IC-21 macrophages bound P815, RBL5, and EL-4 murine tumor cells with high avidity, as measured by the inverted centrifugation method. Tumor binding by IC-21 macrophages was competitively inhibited by crude membrane vesicles prepared from tumor cells but not by cell membranes prepared from nontransformed splenic leukocytes, suggesting that this process was mediated by tumor-specific binding sites. IC-21 macrophages and primary cultures of pyran copolymer-elicited peritoneal macrophages demonstrated similar tumor binding avidity, kinetics, saturability, and metabolic requirements for optimal high avidity tumor binding. However, compared with primary cultures of pyran copolymer-elicited peritoneal macrophages, IC-21 macrophages bound 4-fold more tumor cells and were more homogeneous for tumor binding capability. Finally, one third of maximal tumor cell binding by IC-21 macrophages was completed within 5 min of contact with tumor, suggesting that IC-21 macrophages constitutively expressed some high avidity tumor binding sites. Their stable and homogeneous capability for binding tumor cells and their ease of growth make the IC-21 macrophage cell line a potentially valuable model for elucidating the molecular mechanisms responsible for selective high avidity tumor binding by subpopulations of activated macrophages.