The potential effects of free circulating antigen on the ability of monoclonal antibodies to target tumors in vivo were investigated. Tumor models consisted of HCC, NuE and PLC cell lines producing AFP xenografted in nude mice, and the NuE-treated mouse designated as the NuE-bearing mouse injected with AFP prior to the administration of antibody. Immunoscintigraphy and biodistribution were evaluated by using 125I-labeled monoclonal antibody 19F12 raised against AFP. Gel chromatography analysis of plasma from the PLC-bearing mouse which excreted 400 ng AFP/ml in blood injected with 125I-19F12 indicated that all injected antibody 19F12 formed an immune complex in plasma. No immune complex was present in plasma from the NuE-bearing mice, where blood AFP levels were 7 ng/ml, while the intact antibody was found to remain partly in plasma from the NuE-treated mouse. Radioactivities in the whole body of NuE-bearing and NuE-treated mice eventually cleared at the same rate. Our experimental results indicated that the endogeneous circulating antigen retained the antibody in the whole body for a longer period. The ability of monoclonal antibodies to target tumors was influenced not only by how much antigen was present but also by how rapid the antigen was cleared in the blood.