Partially quaternized poly[thio-1-(N,N-diethyl-aminomethyl) ethylene]s, Q-P(TDAE)x with x indicating the percentage of quaternized subunits, have been proposed as potential carriers for drugs insoluble in water. However these cationic polyelectrolytes form emboli upon intravenous administration. In order to study the mechanism, Q-P(TDAE)11 was incubated in vitro with red blood cells (RBCs) suspended in various aqueous media such as autologous plasma, autologous serum, albumin dissolved in phosphate buffer, plasma–serum mixtures and Tris buffer. The deformability of the RBC membrane studied by viscometry was not affected by the polycation. Q-P(TDAE)11-induced hemagglutination was studied by optical microscopy. It depended on the polymer concentration and on the presence of plasma proteins. As ghosts were formed in some cases, hemolysis was investigated by measuring potassium and hemoglobin released from RBCs. Fibrinogen and serum proteins, except albumin, protected RBCs from hemolysis. Moreover the order of addition of the suspension components modulated dramatically the Q-P(TDAE)11-induced hemolysis. Addition of Q-P(TDAE)11 to whole blood caused hemolysis whereas addition of the polymer to plasma prior to contact with RBCs did not affect the cell integrity. In contrast, addition of the polymer to RBCs suspended in albumin solution caused greater hemolysis than the addition to whole blood, and the contact between Q-P(TDAE)11 and albumin prior to RBC addition still enhanced cell lysis. Two conclusions can be drawn from these observations: (i) Q-P(TDAE)11 induces both hemagglutination, probably through electrostatic interaction, and hemolysis, because Q-P(TDAE)11 disrupted the RBC lipid bilayer; (ii) proteins can decrease or increase the deleterious effects of Q-P(TDAE)11 on RBCs.