A protein antigen, bovine serum albumin (BSA), was covalently linked to the surface of preformed large unilamellar vesicles composed of phosphatidylcholine, cholesterol, and N-[4-(p-maleimidophenyl) butyryl] phosphatidylethanolamine (MPB-PE). The interaction between thiolated BSA and MPB-PE resulted in the production of a protein-liposome conjugate via the formation of an irreversible covalent bond. Mice immunized with liposome-coupled BSA were found to generate a vigorous BSA-specific plaque-forming cell (PFC) response. No significant response was observed in control animals given simultaneous, but separate injections of thiol-BSA and liposomes. Thus, there seems to be a need for successful and stable linkage between the antigen and the carrier. The elicitation of an optimal antigen-specific PFC response was also found to require the vesicle surface to be coated with a certain minimum distribution of the antigen. Results of this study demonstrate that the covalent coupling of a protein antigen to the liposome surface is very effective in potentiating the protein-specific antibody response and the immunogenicity of the conjugate is dependent on the epitope density of the antigen.