Although immune memory often lasts for life, this is not the case for certain vaccines in some individuals. We sought a mechanism for this phenomenon by studying B cell responses to phycoerythrin (PE). PE immunization of mouse strains with Igh^b immunoglobulin (Ig) variable heavy chain (V_H) genes elicited affinity-matured switched Ig memory B cells that declined with time, while the comparable population from an Igh^a strain was numerically stable. Igh^b strains had larger numbers of PE-specific naive B cells and generated smaller germinal center responses and larger numbers of IgM memory cells than the Igh^a strain. The properties of PE-specific B cells in Igh^b mice correlated with usage of a single V_H that afforded high-affinity PE binding in its germline form. These results suggest that some individuals may be genetically predisposed to generate non-canonical memory B cell responses to certain antigens because of avid antigen binding via germline-encoded V_H elements.