Humoral immunity against pathogens relies upon the germinal center (GC), which coordinates the production of high-affinity antibody-secreting cells and the formation of long-lasting memory B cells. The GC developmental program is finely regulated by epigenetic modifiers during an immune response to pathogens; however, persistent infections subvert these mechanisms for their own benefit. Indeed, chronic infections are correlated to inadequate antibody responses and a generalised suppression of B cell memory populations. Polycomb repressive complexes represent a class of histone modifiers that exert their enzymatic activity by maintaining the silenced state of target genes through the deposition of methyl or ubiquitin groups on histone proteins. We hypothesised that the Polycomb group member EED regulates niche-specific GC processes. We therefore investigated the activity of EED in B cell differentiation during immune responses towards acute and chronic infections. Our results demonstrated that conditional deletion of EED in mature B cells dysregulated GC development in T-dependent responses following immunisation or acute viral infection. In contrast, the deletion of EED in mice infected with the chronic LCMV Docile strain or the malaria parasite P. Chabaudihad limited effect on GC B cell number, resulting in a GC response similar to that in acutely infected wild-type mice. To investigate molecular differences between acute and chronic GC responses, we utilised genome-wide scale approaches. Wild-type and EED-deleted mice were infected with either acute or chronic LCMV strains and sort-purified GC B cells were analysed by assay for transposase-accessible chromatin (ATAC)-seq and RNA-seq to establish chromatin conformation and gene expression profiles in either resolving acute or chronic infection. Together, revealing fundamental epigenetic differences in chronic B cell responses may open up new therapeutic interventions by using small molecule inhibitors to target dysregulated histone-modifying complexes.