The emergence of Vibrio cholerae (Vc) lipopolysaccharide (LPS) as a lead protective antigen for a cholera subunit vaccine has increased the interest in what type of B cell is best suited to generate anti-Vc LPS antibodies. A related question is what form of LPS is the most immunogenic. C57Bl/6 (B6) neonatal mice (10 days old) whose marginal zone (MZ) B cell compartment is still maturing and two lines of knockout mice that either lack the signaling mechanism required for the maturation of MZ B cells or that lack a receptor required for MZ B cell retention in the MZ were used to determine the role of MZ B cells in anti-Vc LPS antibody responses. Data support the conclusion that MZ B cells play a significant role in the anti-Vc LPS antibody response. Serum and vibriocidal antibody titers also depend on whether the Vc LPS is purified or bacterial cell-associated. New perspectives are needed to build a universal cholera vaccine. © 2013 Federation of European Microbiological Societies.