The use of polymerase chain reaction (PCR) for routine detection of clonal immunoglobulin heavy-chain (IgH) gene rearrangements represents an attractive alternative to Southern hybridization analysis not only because PCR protocols are quicker and simpler, but also because of the ability to analyze very small population of cells in search of minimal residual disease. This can be especially important for the detection of clonal malignant cells in locations other than bone marrow or peripheral blood. We describe a case in which central nervous system involvement, a very rare complication of chronic lymphocytic leukemia, was confirmed by PCR analysis for IgH genes rearrangement of the lymphocytes found in cerebrospinal fluid. The cerebrospinal fluid and the peripheral blood lymphocytes (obtained from archival cytospins stored at the time of diagnosis, 5 years before) presented an identical IgH gene rearrangement, as shown by sequence analysis. Thus, the use of PCR for IgH genes rearrangement can be very useful in the detection of monoclonality in samples with a small number of cells and in the confirmation of the common origin of B cells in different specimens of the same patient.