Memory B cells (Bmems) may either: (1) rapidly differentiate into short-lived PCs in subcapsular proliferative foci (SPF) and secrete antibodies of the original specificity and affinity; or (2) re-enter secondary germinal centers (GCs) and further diversify their B cell receptor (BCR) to improve their affinity and broaden their specificity for antigenic variants. These 2 cell fates were previously thought to be predetermined by cell-intrinsic programmes, for example as specified by immunoglobulin isotype switching and the expression of certain cell surface molecules. However, using a model antigen system in which Bmems are reactivated in situ without the need for cell isolation, ex vivo manipulation and secondary transfer, we show that the location of antigen encounter can also impact on B cell fate choice. We show in mouse models that lymph nodes draining the site of primary vaccination harbour a subset of Bmems that reside in the subcapsular niche, generate larger recall responses, and are more likely to re-enter GCs compared with circulating Bmems in non-draining lymph nodes. This location-dependent recall of Bmems into the GC is dependent on ‘primed’ subcapsular sinus macrophages (SSMs) in the subcapsular niche. We show that this boosting effect was antigen-independent and could be mimicked by ‘priming’ of the non-draining lymph node with non-cognate antigen. In healthy human participants, boosting of the BNT162b2 vaccine in the same arm that had been primed generated more rapid secretion of broadly neutralizing antibodies, GC participation, and clonal expansion of SARS-CoV-2-specific B cells than boosting of the opposite arm. These data reveal an unappreciated role for the site of antigen encounter and ‘primed' draining lymph node SSMs in Bmem cell fate determination.