CD44H is the principal cell surface receptor for hyaluronate, which is a major glycosaminoglycan of the extracellular matrix. Expression of CD44H is enhanced in a variety of malignant tumors and correlates with tumor aggressiveness, supporting the notion that interaction between CD44H and hyaluronate may play an important role in tumor growth and dissemination. In this report we show that in vivo tumor formation by human lymphoma Namalwa cells, stably transfected with CD44H, can be suppressed by a soluble human CD44H-immunoglobulin fusion protein. Disruption of the interaction between CD44H and its physiologic ligands may provide a novel strategy for controlling tumor growth in vivo.