Therapeutic targeting of soluble molecules such as cytokines can be achieved with monoclonal antibodies (mAb). Anti-IL-6 mAb have been shown to form circulating complexes, resulting in the increase of the half-life of the cytokine in vivo. In IL-6-related diseases, the soluble human IL-6 receptors (shIL-6R), which have been shown to possess strong agonist activity, circulate in the plasma at a high concentration and must be neutralized. Their clearance was studied in mice that had been made to express circulating shIL-6R after i.p. grafting of mouse thymoma cells transfected with a gene coding for shIL-6R, treated with various anti-shIL-6R mAb recognizing different epitopes of the molecule. Injection of one anti-hIL-6R mAb stabilized the short-lived hIL-6R and led to their accumulation. The same result was observed when two mAb directed against two different epitopes of the hIL-6R were used. Clearance of the receptors was only achieved when three mAb specific for three different epitopes were injected. A permanent clearing of the hIL-6R could be obtained by repeated injections of the clearing mixture. No correlation was found between the ability of the mAb to clear the sIL-6R and to immunoprecipitate them in agarose gel. The F(ab')2 fragments lost the clearing ability of the intact mAb. These results clearly show that therapeutic clearance of sIL-6R by mAb need at least three mAb directed against three different epitopes of the molecule, a conclusion which is likely to apply for clearing any soluble target molecule.