Liposomal model membranes, which were prepared with sphingomyelin, cholesterol, and dicetylphosphate, and sensitized by incorporation of either dinitrophenyl-epsilon-aminocaproylphosphatidylethanolamine (DNP-Cap-PE) or fluoresceinthiocarbamylphosphatidylethanolamine (Fl-PE), can induce a hapten-specific humoral response when administered to AKR mice in saline. The magnitude of the response (as measured by the appearance of direct plaque forming cells in the spleen and/or serum antibody titer) is dependent on liposomal dose, the epitope density of the PE derivative in the liposomes, and the time after immunization. In the case of DNP-Cap-PE sensitized liposomes, only a minor IgG response (as measured by the production of indirect plaques or mercaptoethanol-resistant antibody) could be detected after either primary or secondary immunization. Together with the finding that mice deficient in, or depleted of, thymus-derived (T) lymphocytes respond to liposomes containing DNP-Cap-PE, the available data indicate that these liposomes are primarily T cell-independent immunogens. The liposomes are also immunogenic in other inbred mice strains (differing in H-2 haplotype), although the magnitude of the response varies sufficiently to suggest the existence of high, intermediate, and low responders. On the basis of this preliminary survey, further examination of the possibility that the immunogenicity of liposomes may be under genetic control seems warranted.