Malignant peripheral nerve sheath tumors (MPNST) develop in approximately 10% of neurofibromatosis type-1 patients and are a major contributing factor to neurofibromatosis-1 patient mortality and morbidity. MPNSTs are multidrug resistant, and thus long-term patient survival rates are poor after standard doxorubicin or multiagent chemotherapies. We show that the hyaluronan receptor CD44 forms complexes with multidrug transporters, BCRP (ABCG2) and P-glycoprotein (ABCB1), in the plasma membrane of human MPNST cells. Small hyaluronan oligosaccharides antagonize hyaluronan-CD44-mediated processes and inhibit hyaluronan production. Treatment of MPNST cells with the hyaluronan oligomers causes disassembly of CD44-transporter complexes and induces internalization of CD44, BCRP, and P-glycoprotein. Consequently, the oligomers suppress drug transporter activity and increase sensitivity to doxorubicin treatment in culture. In vivo, systemic administration of hyaluronan oligomers inhibits growth of MPNST xenografts. Moreover, the oligomers and doxorubicin act synergistically in vivo, in that combined suboptimal doses induce tumor regression to a greater extent than the additive effects of each agent alone. These findings indicate that constitutive hyaluronan-CD44 interactions contribute to drug transporter localization and function at the plasma membrane, and that attenuating hyaluronan-CD44 interactions sensitizes MPNSTs to doxorubicin in vitro and in vivo. These results also show the potential efficacy of hyaluronan oligomers, which are nontoxic and nonimmunogenic, as an adjuvant for chemotherapy in MPNST patients.