To investigate the clinical implications of germline Cµ transcription, the splice region between the 3′ end of the enhancer and the first exon of immunoglobulin germline μ was analyzed by RT-PCR in 63 samples from 59 patients with leukemia. Immunophenotypes of 33 samples from patients with acute leukemia were analyzed using a panel of these monoclonal antibodies: anti-immature/stem cell (HLA-DR, CD34); anti-mature myeloid (CD33, CD15); anti-T lymphoid (CD2, CD3, CD5, CD7, CD8), and anti-B lymphoid (CD10, CD19, CD20). Of the 63 samples, 33 (52%) contained germline Cµ transcripts: 2/2 patients with chronic lymphocytic leukemia; 17/26 (65.4%) patients with acute myeloblastic leukemia; all 4 patients with chronic myelogenous leukemia in blast crisis and 1 in accelerated phase; 9/12 patients with acute lymphocytic leukemia. A clear correlation between germline transcripts and HLA-DR expression was observed among germline-positive cases (p < 0.01). Cµ expression and response to therapy clearly indicated that germline-µ-positive leukemia patients responded poorly to chemotherapy and had a worse clinical prognosis compared with Cµ-negative patients (p < 0.01). After two courses of chemotherapy, 7/9 Cµ-negative patients achieved complete remission compared to only 7/29 Cµ-positive patients (p < 0.01). We conclude that the gene-regulating immunoglobulin germline Cµ may be amplified in myeloid and B-lymphoid cells during leukemogenesis. Such genetic changes may be correlated with cellular terminal differentiation injury, resistance to chemotherapy and uncontrolled malignant cell proliferation.