In a model for persistent infection, Epstein-Barr virus (EBV) uses the germinal center (GC) reaction to establish persistence in memory B cells. To study whether EBV adopts to normal B cell differentiation processes also in EBV-associated lymphoproliferative diseases, we micromanipulated EBV(+) cells from biopsies of five patients with post-transplantation lymphoproliferative disease (PTLD) and one unusual Hodgkin lymphoma with many small EBV(+) cells, and analyzed rearranged V genes of single cells. In all cases clonal expansions of EBV(+) B cells were identified. The vast majority of these clones carried mutated V gene rearrangements and a fraction of clones showed ongoing hypermutation. Hence, PTLD likely derive from GC and/or post-GC B cells. In two clones hypermutation occurred in the absence of follicular dendritic and CD4(+) T cells, important interaction partners of normal GC B cells. Furthermore, in one case sustained somatic hypermutation occurred without expression of a functional antigen receptor. Hence, EBV(+) B cells in PTLD can retain or acquire features of GC B cells in an unphysiological setting and may continue to undergo somatic hypermutation uncoupled from normal selection processes, suggesting that EBV interferes with normal B cell differentiation and selection processes in PTLD