Deposition of a fluorophoric material, known as lipofuscin, in retinal pigment epithelium cells has been speculated to be one of the biomarkers of age-related macular degeneration. One of the fluorophores of lipofuscin has been characterized as A2E, a pyridinium bisretinoid. Its cationic nature along with two hydrophobic retinal chains suggests that it can disrupt the membrane integrity by its detergent-like activity and can thus cause cellular damage. With this notion, we studied in detail the interaction between A2E and the model membranes of different lipid compositions using fluorescence steady-state and fluorescence anisotropy measurements. A transition from vesicular to micellar structure occurred upon incorporation of A2E into the lipid bilayer. However, the A2E concentration at which this transition occurred depends on the lipid composition. A lipid mixture containing 10% phosphatidylserine (PS) (close to disc membrane PS content) behaved similarly to a lipid mixture having no PS. In contrast, vesicles containing 20% PS showed significantly different behavior. Membrane solubilization by A2E was also confirmed by vesicle leakage experiments. A2E also showed significant activity in liposome-mediated gene transfection. A lipid formulation containing 40% A2E and a helper lipid showed plasmid DNA transfection efficiency comparable to commercially available transfection reagents with no evidence of cytotoxicity. These results contribute to understanding the mechanism underlying the A2E-induced cellular dysfunction.