We congratulate Omoti and Omoti for their timely review of Richters Syndrome (RS) (Omoti & Omoti, 2008). In their discussion of pathogenesis, the authors discuss the potential role of Epstein-Barr Virus (EBV) as an aetiological agent in some cases of RS, as also appears to be the case in a variety of other lymphoid neoplasms (Gandhi, 2006). They state that this supports B-cell lymphomas being defined ‘by the combination of transforming events and the stage of differentiation at which a B-cell is a target for transformation’. If we take this explanation to its rationale conclusion, it relies on the assumption that, during the process of transformation, the final phenotype of the RS cell reflects that of the original infected cell. Since malignant transformation of a low-grade lymphoproliferative disorder to a high-grade one is a multi-step and multi-factorial process, such an assertion, although useful as a means of classification, is almost certainly overly-simplistic. However, where we take particular issue is in the authors statement that EBV primarily ‘infects the long-lived memory B-cells and not naïve B-cells’. This contention is based on a misinterpretation of their cited references (Macsween & Crawford, 2003; Hochberg et al, 2004; Betts, 2006). A strong body of data supports the notion that EBV infects naïve tonsillar B-cells. EBV infection provides activation of the newly infected B-cells so that they can undergo a germinal centre (GC) reaction, characterized by somatic hypermutation and class-switching (Klein & Dalla-Favera, 2008) and differentiate into memory B-cells that egress into the circulation (Babcock et al, 2000). In this model, infected peripheral memory B-cells are the principal viral reservoir. By contrast, the normal cell counterpart of high-risk (i.e. unmutated immunoglobulin gene) Chronic Lymphocytic Leukaemia (CLL) has phenotypic features of B-cells originating from the marginal zone that appear not (by virtue of their unmutated status) to have undergone GC processing. Indeed, a recent report in this journal clearly demonstrated it is these cases of CLL that are at greatest risk of RS (Rossi et al, 2008). In conclusion, we totally agree that the precise role of EBV infection in RS remains to be established (Gandhi & Khanna, 2006). However, the existing data would point to naïve B-cells being the principle site of primary EBV infection, and that transformation to RS is more likely in cells that have yet to undergo the GC reaction.