Liposomes are used for in vitro or in vivo vectorization of drugs, proteins, or nucleic acids. However, the main problem with the application of liposomes for this purpose is their low stability in contact with blood serum. In this article, interactions between the whole serum and anionic liposomes, both bare and covered with strong polycations, were studied. The polycations of different chemical structures were prepared by the modification of poly(allylamine hydrochloride) (PAH). Dynamic light scattering (DLS), zeta potential and transmission cryo-electron microscopy (cryo-TEM) measurements showed that the adsorption of the polycations on the anionic liposomes induced a reversible aggregation of vesicles. The stable isolated polyelectrolyte-covered vesicles were obtained after the addition of sufficient amounts of the polycations. The effect of full serum on the morphology and stability of the polycation-coated liposomes was studied using cryo-TEM and a fluorescence method. The cryo-TEM analysis revealed that the introduction of serum caused the osmotic-driven destabilization of the bare liposomes or formation of twinned vesicles. Due to these processes the liposomes lost most of their content immediately after serum addition. The polycation-covered liposomes showed improved stability in the presence of serum. Partial deflation of the vesicles was observed, however, the loss of the content was significantly limited. The effect of the polymer structure, especially the position of the charged groups with respect to the main polymer backbone, on the stabilization of the polycation-covered liposomes in the presence of serum was discussed.