Despite recent identification of a recurrent chromosome 6q21 deletion in sporadic Waldenstrom's macroglobulinemia (WM), elucidation of the molecular pathogenesis of WM remains challenging. In contrast to the growing body of cytogenetic studies in sporadic WM, there have been virtually no informative studies of familial WM. The authors therefore undertook conventional and molecular cytogenetic evaluation of 18 patients with familial WM and 3 patients with immunoglobulin (Ig) M monoclonal gammopathy (IgM-MG) from 15 families to determine the nature and extent of chromosomal abnormalities associated with familial WM. The frequency and distribution of chromosomal changes in familial WM resembled those in sporadic WM, including lack of IgH rearrangements and t(9;14); however, we detected del6q21 in only 1 patient. Occasional findings appeared to be novel; however, none were recurrent, and their significance remains unclear. Only one abnormality found in bone marrow specimens was detected in parallel peripheral blood lymphocyte studies, suggesting that most abnormalities represented somatic changes. Although they must be viewed in light of the hypoproliferative nature of WM, our results suggest that further progress in delineating the genetic determinants of WM susceptibility might be gained from alternative approaches such as candidate gene or linkage analysis.