The potential use of liposomes as a delivery system is still limited by the poor understanding of the interaction mechanisms of liposomes underlying with biological media. Interaction between liposomes and protein is important for the structure and function of cells. In the present work, the interaction between collagen and dipalmitoyl phosphatidylcholine (DPPC) liposomes was studied by solubilization using a nonionic detergent, octylglucoside (OG), as well as a monolayer technique. The solubilization of the liposomal membrane was found to proceed in three stages of transition from the vesicular form to the mixed micellar form. Moreover, the amount of detergent needed to completely solubilize the liposomal membrane was increased after the incubation of liposomes with collagen, indicating an increased membrane resistance to the detergent and hence, a change in the natural membrane permeation properties. The addition of collagen in the sub-phase of different monolayer films induced a considerable shift towards a larger area/molecule in the compression-isotherm curves. This is either due to the insertion of collagen into the monolayer via its hydrophobic residues or to adsorption causing a protein layer to be located parallel to the lipid monolayer. It was concluded that collagen significantly altered the physical state of the liposome membrane, which may be attributed to collagen interaction with the liposomal surface and/or to its incorporation within the bilayer membrane.