The destabilization effect of a hydrophilic polymer, poly-alpha,beta-[N-(2-hydroxyethyl)-L-aspartamide] (PHEA), and an amphiphilic polymer, PHEA-g-poly(2,2-dimethyltrimethylene carbonate) (PHEA-g-PDTC), on phosphatidylcholine vesicles has been investigated. The hydrophilic polymer PHEA has a strong destabilizing effect on the liposomes and induces immediate vesicular membrane leakage and aggregation, while the destabilizing effect of the amphiphilic polymer PHEA-g-PDTC is weaker. The in situ observation on shape transformations of a vesicle indicates that the addition of PHEA increases the amplitudes of fluctuations of the vesicle membrane, finally leading to the burst of the vesicle. The existence of hydrogen bonding between the polymers and the liposome membranes is mainly responsible for inducing the destabilization. The molecular structure of the polymers, such as the stiffness of the polymer backbone and the spacer connecting the hydroxyl group with the backbone, greatly affects the interaction between the polymers and the vesicles.