Natural lipid headgroups contain a few types of metal ligands, such as phosphate, amine, and serine, which interact with metal ions differently. Herein, we studied the binding between Cu2+ and liposomes with four types of headgroups: phosphocholine (PC), phosphoglycerol (PG), phosphoserine (PS), and cholinephosphate (CP). Using fluorescently headgroup-labeled liposomes, Cu2+ strongly quenched the CP and PS liposomes, whereas quenching of PC and PG was weaker. Dynamic light scattering indicated that all of the four liposomes aggregated at high Cu2+ concentrations, and ethylenediaminetetraacetic acid (EDTA) only restored the original size of the PC liposome, implying fusion of the other three types of liposomes. The leakage tests revealed that the integrity of PC liposomes was not affected by Cu2+, but the other three liposomes leaked. Under TEM, all of the liposomes show a positive-stain feature in the presence of Cu2+ and Cu2+-stained individual liposomes with a short incubation time (<1 min). The oxidative catalytic property of Cu2+ was also tested, and a tight binding by the PS liposome inhibited the activity of Cu2+. Finally, a model of interaction for each liposome was proposed, and each one has a different metal-binding and interaction mechanism.