The production of antibody and formation of immunological memory underpins vaccine success. Yet, chronic viral infections result in an inadequate humoral response, in which high-affinity neutralising antibody production is delayed and the immune memory repertoire is ineffective. Little is known about the mechanisms underpinning this dysregulation. We therefore utilised acute or chronic strains of lymphocytic choriomeningitis virus (LCMV) to investigate B cell behaviour in vivo during chronic infections. Using a novel tetramer to track antigen-specific B cells, our data indicated that chronic infection altered epigenetic regulation of B cell fate. We focused on two members of the Polycomb repressive complexes PRC1 and PRC2: BMI-1 and EED, respectively. Deletion of EED in B cells resulted in a complete absence of germinal centres (GC)s and B cell memory following immunization or acute viral infection, whereas BMI-1 was required for plasma cell but not GC formation. Surprisingly, Eedf/fCd23Cre/+ mice infected with the chronic strain of LCMV were able to mount GC responses. BMI-1 was upregulated in GC B cells of chronically-infected mice, and its deletion resulted in an enhanced and rapid ability to clear virus. Deep-sequencing revealed key differences in chromatin accessibility and gene expression profiles of B cells responding to acute vs chronic infection. Together, our data demonstrates that epigenetic regulation of B cell differentiation in chronic infection is distinct from acute infection or protein immunisation. Understanding the molecular events that may sustain dysfunction lays the foundation for improving therapeutic interventions in chronic infectious diseases.