Copper and mercury play a toxic role in several pathological processes, including neurodegeneration. The structural effects of Cu2+ and Hg2+ on cell membranes were studied through their interactions with human erythrocytes, isolated resealed membranes, and molecular models. Both ions induced shape changes in erythrocytes, which took the form of echinocytes due to location of the ions in the outer monolayer of the erythrocyte membrane. Fluorescence spectroscopy analysis revealed that the interactions occurred in the polar region of me membrane, that is, at the hydrophobic-hydrophilic interface. X-ray experiments indicated that both ions interacted with the polar groups of phospholipids located in the outer monolayer of the erythrocyte membrane. Finally, electrophysiological measurements of toad skin showed that Cu2+ and Hg2+ inhibited the active transport of ions. The experimental results confirmed the toxicity of both heavy metals on membrane structure and functions.