The immunological profile of lymphoproliferative disorders is usually conserved whatever the involved site, thus allowing a reliable diagnosis from peripheral blood analysis, especially in small lymphocytic lymphoma/chronic lymphocytic lymphoma (SLL/CLL). Here we present a case wherein the cytology and immunophenotype of blood specimen and bone marrow argue in favor of SLL/CLL with a typical Matutes score (5/5), whereas the cyto-histology and immunophenotype of spleen specimen led to the diagnosis of splenic marginal zone B-cell lymphoma (SMZL). Moreover genomic analysis showed that the splenic cells displayed a SMZL signature. Whereas these data suggested the presence of 2 B-cell clones, the study of the mutational status of IgVH gene in blood and spleen demonstrated the presence of a single clone, which likely developed simultaneously along two distinct ways of differentiation according to the anatomic site suggesting here the predominant role of a micro-environmental factor in cell differentiation. Although rare, this kind of event must be kept in mind as a cause of discrepancies between diagnoses from different sites.