The Epstein-Barr virus (EBV) uses nasopharyngeal-associated lymphoid tissue (NALT) as portal of entry to establish life-long persistence in memory B-cells. We previously showed that naïve and memory B-cells from NALT are equally susceptible to EBV infection. Here, we show that memory B-cells from NALT are significantly more susceptible to EBV infection than those from remote lymphatic organs. We identify beta1 integrin, which is expressed highest by naïve B-cells of distinct lymphoid origin and by memory B-cells from NALT, as mediator of increased susceptibility to infection by EBV. Furthermore, we show that BMRF-2-beta1 integrin interaction and the downstream signal transduction pathway is critical for post-binding events. Increase of beta1 integrin expression in peripheral blood memory B-cells provoked by CD40 stimulation plus B-cell receptor cross-linking increased the susceptibility of non-NALT memory B-cells to EBV infection. Thus, EBV seems to utilize the increased activation status of memory B-cells residing in the NALT to establish and ensure persistence.