Background: B cells of patients with non-Hodgkin's lymphoma (B-NHL) harbor specific chromosomal translocations, including t(14; 18), the most common aberration found in this disease. The translocation involves the immunoglobulin (Ig) heavy-chain joining (JH) region gene on chromosome 14 and the BCL2 gene on chromosome 18, resulting in dysregulated expression of the BCL2 gene. The t(14;18) translocation has been thought to occur in the pre- B-cell stage, during the first event of Ig gene rearrangement. Purpose: This study was conducted to investigate the potential involvement of nonlymphoid lineages in B-NHL. Methods: We studied the t(14;18) translocation and other frequently occurring translocations in total bone marrow aspirates of 10 patients with B-NHL, with the use of the fluorescence in situ hybridization (FISH) technique. We also performed cytogenetic analyses on representative bone marrow aspirates from the patients. Moreover, to define which of the major cell lineages present in the bone marrow carry the t(14;18) translocation, we used a series of monoclonal antibodies together with fluorescence-activated cell sorter (FACS) analyses to purify cells positive for CD3 (T cells), CD19 (B cells), CD10 (CALLA-positive cells), CD41a (megakaryocytic cells), CD13 (myeloid cells), and glycophorin A (erythroid cells). The cells of each subgroup underwent FISH analysis with the use of JH and BCL2 probes to detect the t(14;18) translocation. Bone marrow samples obtained from five healthy donors served as controls. Results: Bone marrow cells from eight of the 10 patients studied carried the t(14;18) translocation. When present, the translocation was observed in many or even all of the cell lineages (lymphoid, myeloid, megakaryocytic, and erythroid) present in the bone marrow, including peripheral blood progenitor stem cells; for seven of the eight patients carrying the translocation, it was found in 96%-100% of the unfractionated bone marrow cells as well as in all of the FACS-purified cell fractions in which it could be detected or studied. Conventional cytogenetic analyses performed on representative bone marrow aspirates confirmed the results obtained by FISH analysis. Cells in control bone marrow samples obtained from the five healthy donors were negative for the t(14;18) translocation by FISH analysis. Conclusions: Our findings indicate that the t(14;18) translocation most probably occurs in a very early multilineage progenitor stem cell. Implications: Given that the t(14;18) chromosomal translocation was found in all types of bone marrow cells when only the B cells were malignant, our results suggest that this translocation is not sufficient to induce neoplastic transformation. This finding underscores the need for the development of new approaches for the detection and surveillance of B-NHL.