Two unusual cases of large B-cell lymphoma with predominant splenic and bone marrow (BM) involvement and similar clinical and histopathologic features are described. Both patients presented with nonspecific constitutional symptoms, unexplained cytopenias, and splenomegaly. Splenectomy revealed diffuse red pulp involvement by large B-cell lymphoma. The perisplenic lymph nodes were also involved diffusely with effacement of normal nodal architecture, excluding a diagnosis of intravascular large B-cell lymphoma. BM biopsies revealed striking erythroid hyperplasia without overt morphologic evidence of involvement by lymphoma. Immunoperoxidase staining of the marrow biopsies with antibodies to CD20 and erythroidassociated antigens revealed involvement by large B-cell lymphoma morphologically resembling the early pronormoblasts. In both cases there was prominent, but not exclusive, intravascular/intrasinusoidal lymphomatous marrow infiltration. These cases represent an unusual variant of large B-cell lymphoma with distinctive patterns of splenic and BM involvement. Furthermore, they underscore the difficulties in identifying intrasinusoidal marrow infiltration by lymphoma in H&E-stained biopsy slides and demonstrate that this pattern of marrow infiltration may be seen in cases of large B-cell lymphoma distinct from the intravascular variant. Keywords: diffuse large B-cell lymphoma; intravascular lymphoma; spleen; bone marrow; erythroid hyperplasia; non-Hodgkin lymphoma Diffuse large B-cell lymphoma (LBCL) can involve nodal or extranodal sites; however, initial presentation in the spleen occurs infrequently. 1 Typically when diffuse LBCL involves the spleen it forms discrete tumoral masses within the splenic parenchyma. 2 A recent report detailed other less common patterns of splenic involvement by LBCL including diffuse infiltration of the splenic red pulp. 3 The clinicopathologic features of diffuse LBCL with these unusual patterns of splenic involvement have yet to be fully elucidated. Described herein are the distinctive clinical and histopathologic features of two cases of splenic LBCL with diffuse red pulp infiltration and concurrent involvement of lymph nodes and bone marrow (BM). These cases had strikingly similar clinical presentations chiefly characterized by dyspnea, unexplained cytopenias, and splenomegaly. In both instances, splenectomy performed to alleviate the cytopenias revealed diffuse, homogeneous involvement of the splenic red pulp by diffuse LBCL. Although the pattern of splenic red pulp involvement and the clinical features raised the possibility of intravascular LBCL, in both cases there was parenchymal involvement of splenic hilar lymph nodes, excluding this diagnosis as defined by the most recent WHO criteria. 4 Furthermore, both cases had prominent BM involvement by lymphoma, which was difficult to detect by routine morphologic evaluation of hematoxylin and eosin (H&E)-stained biopsy slides. This difficulty was due both to the presence of prominent erythroid hyperplasia as well as a predominan...