Trypanosoma brucei brucei the causative agent of ngana in cattle, is non-infectious to humans because of its sensitivity to the cytolytic activity of normal human serum(1). The toxin in normal human serum is human haptoglobin-related protein (Hpr)(2-5) which is found either as an apolipoprotein associated with a minor subclass of high-density lipoprotein (HDL), named trypanosome lytic factor (TLF1)(6-8), or as an unstable, high-molecular-mass protein complex known as TLF2 (refs 5, 9-12). TLF-mediated lysis of T. b. brucei requires binding, internalization and lysosomal targeting(13). The human sleeping-sickness trypanosome, Trypanosoma brucei rhodesiense is resistant to TLF. Our studies reveal that resistant trypanosomes fail to endocytose TLF yet continue to bind TLF through cell-surface receptors. On the basis of these results, we conclude that one mechanism of resistance of human sleeping-sickness trypanosomes to human serum is decreased internalization of receptor-bound TLF.