Unlike Trypanosoma brucei brucei, Trypanosoma brucei gambiense resists killing by apolipoprotein L1 (apoL1), which associates with the serum complexes trypanolytic factor 1 (TLF1) and TLF2 and mediates killing after insertion into endosome–lysosome membranes. This study finds that T. b. gambiense resistance is conferred by TgsGP, which interacts with membrane lipids via its hydrophobic β-sheets and induces stiffening and increased curvature of endosomal membranes. Reduced sensitivity to apoL1 was also found to be due to increased activity of the parasite protease cathepsin D (which might accelerate apoL1 degradation) and downregulation of the TLF1 receptor HpHbR.