Herein, we demonstrate that Cu2+ binds bivalently to phosphatidylethanolamine (PE), the second most abundant lipid in mammalian cells. The apparent equilibrium dissociation constant, K-DApp, for the Cu2+-PE complex at physiological pH is approximately 2 mu M and is insensitive to the concentration of PE in the membrane. By contrast, at pH 10.0, where PE lipids bear a negative charge, K-DApp decreases with increasing PE content and has a value of 150 nM for bilayers containing 70 mol % PE. The oxidation of double bonds in PE-containing bilayers can, be monitored in the presence of Cu2+. Strikingly, it was found that the oxidation rate is 8.2 times faster at pH 7.4 for bilayers containing 70 mol % PE than for pure phosphatidylcholine (PC) bilayers upon exposure of both to 70 mu M Cu2+ and 10 mM hydrogen peroxide. The rate of oxidation increases linearly with the PE content in the membrane. These results may help explain the high level of lipid oxidation in PE-containing membranes for neurodegenerative diseases and autism where the Cu2+ concentration in the body is abnormally high.