a-haemolysin (HlyA) from E. coli readily lyse erythrocytes from various species of mammals. This lysis is generally accepted to result from receptor-independent insertion of HlyA-pores in the plasma membrane and subsequent swelling caused by influx of cations and water. We have, however, recently shown that HlyA-induced haemolysis in human, murine and equine erythrocytes require ATP release with subsequent P2 receptor and pannexin channel activation. Blockage of P2X7/P2X1 receptors, pannexin channels or scavenging of ATP completely abolish the HlyA-induced haemolysis. Here we report that nucleated snake erythrocytes from Python regius are resistant to HlyA-induced lysis. HlyA concentrations that produce maximal lysis of human erythrocytes have no effect in python, although more than 100 fold increase of the HlyA concentration do provoke considerable haemolysis. Similar results were found for a- toxin from Staph. aureus. The difference in HlyA- sensitivity cannot be accounted for by osmotic resistance as python erythrocytes are more susceptible to small changes in osmolality compared to human. The reduced HlyA sensitivity is not a general feature of all nucleated erythrocytes, as turtle (Trachemys scripta) red blood cells have similar HlyA-sensitivity to humans. Likewise, the difference in HlyA- sensitivity is not caused by impaired purinergic amplification. Inhibition of P2 receptors and pannexin-like channels were equally capable of antagonising HlyA-induced lysis in python erythrocytes. The non-selective P2 receptor antagonist (PPADS, 500 mM) reduced haemolysis by ~90 % and the pannexin blocker (carbenoxolone, 100 mM) by ~80% (at 75% lysis after 60 min). These data implies that python erythrocytes express P2-like receptors, which similar to mammals amplify HlyA-induced haemolysis. The python erythrocytes' remarkable resistance to bacterial pore-forming toxins likely reflects biophysical properties of the plasma membrane reducing the ease of HlyA-insertion. This could potentially be important for pythons susceptibility for gram negative infections.