A total of 106 trephine biopsy specimens with clinical, laboratory and pathology findings corresponding to chronic myeloproliferative disorders (CMPD) were analyzed to reveal the nature of the lymphoid infiltrate in the bone marrow. Histological investigation in 31 chronic myeloid leukemia (CML), 29 CMPDs not otherwise specified (CMPD-NOS), 28 essential thrombocytosis (ET), 15 polycythemia vera (PV) and three chronic eosinophilic leukemia/hypereosinophilic syndrome (CEL/HES) exhibited in 32% various amounts of lymphocytic infiltrate of sparsely to moderately diffuse or nodular types in the bone marrow, but the reactive or coinciding lymphomatous nature could not be revealed by histology alone in the majority of cases. PCR analysis of the immunoglobulin heavy chain (IgH) gene rearrangement was successfully performed in 81 out of the 106 DNA specimens extracted from formol-paraffin blocks. Out of the 81 samples with good-quality DNA, 18 gave a single or double discrete amplification band(s), which was reproducible only in four specimens. Sequencing finally proved monoclonal B-cell population of both pre- and postfollicular origin in all four samples (5%), one CML and three CMPD-NOS. Detailed clinical and pathological investigations indicated overt B-cell malignant lymphoma with clonal relationship to the CMPD in two out of these four patients. We conclude that detailed molecular analysis of IgH gene rearrangement in bone marrow samples of CMPD patients is needed to identify the true monoclonal B-cell infiltration, which-even without overt malignant lymphoma-may occur in this group of disorders. Modern Pathology (2004) 17, 1521-1530, advance online publication, 16 July 2004; doi:10.1038/modpathol.3800225.