Two cases of malaria related chronic splenomegaly, one with tropical splenic lymphoma with villous lymphocytes (TSLVL) and the other with hyperreactive malarial splenomegaly (HMS) were analyzed by cytology, histology, karyotyping, immunophenotyping, and polymerase chain reaction (PCR) for detection of bcl-2/JH and FR3/JH rearrangements on blood and bone marrow samples, at diagnosis and 12 months after malarial prophylaxis. The reported data suggest that the detection of FR3/JH rearrangement might contribute to the diagnosis of TSLVL in patients with malaria related chronic splenomegaly, for whom bcl-2/JH rearrangement may be a common molecular event.