Significant numbers of villous lymphocytes were noted in the blood of patients with a clinical diagnosis of hyperreactive malarial splenomegaly (HMS) in Ghana. Demographic and haematological data were recorded from 22 patients with massive splenomegaly. Additional investigations included lymphocyte immunophenotyping, protein electrophoresis and immunoglobulin gene rearrangements. Although all patients had over 30% villous lymphocytes and no leucocytosis, 7 had no evidence of a monoclonal disorder. Immunophenotyping and the presence of monoclonal lymphocytes identified 3 further patients with B-cell splenic lymphoma with villous lymphocytes (B-SLVL). HMS and SLVL co-existed in the same, predominantly female, patient population and were indistinguishable except by molecular analysis of lymphocytes. The discovery of the uncommon villous lymphocytes in both non-malignant and malignant disorders in the same geographical area suggested that HMS and SLVL are pathophysiologically related. In Caucasians with SLVL the malignant cells arise from B-cells that have undergone antigen selection. We postulate that the excessive proliferation of polyclonal B-lymphocytes, driven by frequent exposure to malaria, predisposes to the emergence of a malignant lymphoma, B-SLVL, in tropical West Africa.