The interaction between lipids and metal ions is important for metal sensing, cellular signal transduction, and phosphate group of lipids for metal binding, we herein highlight its importance. Phosphocholine (PC) and its headgroup inversed choline phosphate (CP) lipids were used to prepare liposomes. From dynamic light scattering (DLS), Zn2+ causes significant aggregation or fusion of the CP liposomes, but not PC liposomes. The size change induced by Zn2+ is not fully reversed by adding EDTA, implying liposome fusion induced by Zn2+. Isothermal titration calorimetry (ITC) shows that binding between Zn2+ and CP liposomes is endothermic with a K-d of 110 mu M Zn2+, suggesting an entropy driven reaction likely due to the release of bound water. In comparison, no heat was detected by titrating Zn2+ into PC liposomes or Ca2+ into CP liposomes. Furthermore, Zn2+ causes a transient leakage of the CP liposomes, and further leakage is observed upon removing Zn2+ by EDTA. Transmission electron microscopy (TEM) with negative stained samples showed multilamellar CP lipid structures attributable to Zn2+ sandwiched between lipid bilayers, leading to a proposed reaction mechanism. This work provides an interesting system for studying metal interacting with terminal phosphate groups in liposomes, affecting the size, charge, and membrane integrity of the liposomes.