[en] Poly(2-dimethylamino-ethylmethacrylate) (PDMAEMA), a cationic polymer, has been widely reported as a nonviral carrier. Despite the fact that the cytotoxicity of this polymer has been extensively studied, there is a lack of information about its blood compatibility. Hence, this work evaluates the hemocompatibility of free-form PDMAEMA homopolymers differing in molecular weight (Mw) with or without a poly(ethylene glycol) (PEG) sequence in the form of a palm tree-like structure. Poly(ethylenimine) (PEI) was used as a reference in order to compare its hemoreactivity. Hemagglutination, hemolysis, platelet number, blood coagulation, and the complement systems were assessed in normal human whole blood according to the ISO 10993-4. Results showed that Mw, concentration, and incubation time strongly affected the hemocompatibility of the polymers evaluated. Our in vitro observations highlight that PDMAEMA homopolymers interacted strongly with the surface of the red blood cells but not with the inner structure of the membrane, while PEI behaved in the opposite way. No clear correlation has been evidenced between PDMAEMA-induced hemagglutination, PEI-induced hemagglutination, and hemolysis. Interestingly, if these polyelectrolytes strongly affect the platelets and blood coagulation cascades in a dose dependent way, none of them significantly affects the complement system. Our work reveals new knowledge on the toxicology of 2 families of polycations largely explored for gene delivery and on their mechanisms of cellular and humoral interactions.