B-1 lymphocytes comprise a unique subset of B cells that differ phenotypically, ontogenetically, and functionally from conventional B-2 cells. B1 cells play an important role in innate immunity by contributing to the first line of defense against bacterial and parasite infection. A frequent specificity of the antibody repertoire of peritoneal B-1 cells is phosphatidylcholine. Liposomes containing phosphatidylcholine have been studied as adjuvants and their interaction with dendritic cells and macrophages has been demonstrated. However, the role of B-1 cells in the adjuvanticity of phosphatidylcholine liposomes has not been explored. Here, we studied the contribution of B-1 cells to the humoral response against ovalbumin (OVA) encapsulated into dipalmitoylphosphatidylcholine (DPPC) and cholesterol-containing liposomes and the macrophage polarization induced by these vesicles. BALB/xid mice, which are deficient in B-1 cells, showed quantitative and qualitative differences in the anti-OVA antibody response compared to wild type animals after immunization with these liposomes. The OVA-specific immune response was complete reestablished in the BALB/xid mice when they were reconstituted with B-1 cells from the naïve BALB/c mice. Similarly, the DPPC liposomes administration by intraperitoneal route increased the antibodies production, the cellular surface expression of MHC-II and CD86 molecules and decreased the IL-10 secretion of B-1 cells from BALB/c mice. These findings, allowed concluding that phosphatidylcholine-containing liposomes active B-1 cells by inducing a favorable phenotype to antigen presentation with less suppressor ability. Moreover, our results indicate that after internalize DPPC liposomes, B-1 cells migrate from the peritoneal cavity to the spleen. We also demonstrated that phosphatidylcholine significantly contributed to the immunogenicity of the liposomes because DPPC liposomes stimulated the anti-OVA response more effectively than dipalmitoylphosphatidylglycerol vesicles. Likewise, the contribution of B-1 cells to the adjuvants properties of DPPC liposomes is also mediated by anti-phosphocholine IgM antibodies secreted by these stimulated cells. These antibodies improved the liposomes internalization by macrophages and enhanced the antibodies responses specific to OVA. On the other hand, the immunization of BALB/c mice with DPPC/OVA liposomes induced an M2-like peritoneal macrophage pattern, reprogrammable to M1 phenotype after LPS stimulation, with the involvement of B-1 cells. To sum up, we presented evidences for a cognate interaction between B-1 cells and phosphatidylcholine-liposomes, modulating the immune response to encapsulated antigens and macrophage phenotype induced by liposomal formulation. This provides a novel targeting approach to assess the role of B-1 cells in humoral immunity.