B-cell chronic lymphocytic leukemia (B-CLL) and multiple myeloma (MM) are chronic B-cell malignancies that represent different stages of B-cell maturation. Occasionally, both diseases are present in the same patient, and this raises the question of clonal associations between the two neoplasms. We here report on two patients with concomitant B-CLL and MM. Clonal chromosomal abnormalities in both lymphocytic cells and plasma cells were studied by interphase fluorescence in situ hybridization (FISH) using a panel of 24 chromosome- and region-specific DNA probes. In the first patient, cytogenetics revealed 47, X, t(Y;22)(p11;q10), +12, dell4(q21q32). By FISH, +12 was present in lymphoid cells, but not in plasma cells. MM cells were characterized by multiple chromosomal gains (1, 11q23) and losses (5q, 10, 13q14, 15, 17p13, Y), which were all undetectable in lymphoid cells. The second patient, in whom no clonal abnormalities were obtained by conventional cytogenetic analysis, had lymphoid cells with loss of 8q24 by FISH. In contrast, evidence for a gain of 8q24 (consistent with amplification of c-myc) was obtained in 13% of plasma cells. Plasma cells were further characterized by gains of chromosomes 1, 3, 11, 18, and Y. We thus conclude that this comprehensive molecular cytogenetic analysis demonstrates the existence of two clonally distinct B-cell malignancies in both patients.