Persistent polyclonal B-cell lymphocytosis is a rare, benign lymphoproliferative disorder characterized by a stable, polyclonal CD19-positive CD5-negative lymphocytosis, the presence of binucleated lymphocytes in peripheral blood, and a polyclonal increase in serum immunoglobulin-M that may occasionally be accompanied by splenomegaly. Histopathologic diagnosis of these splenectomy specimens is difficult because of the massive spleen infiltration and the rarity of the descriptions of this condition. We describe the histopathologic findings from 2 splenectomy specimens. These included a partially preserved architecture with infiltration of the red pulp by small lymphocytes and partial replacement of the white pulp. Suggestions for identifying the disorder are made.