The BCR/ABL tyrosine kinase inhibitor imatinib mesylate (Gleevec, STI571; Novartis, Basel, Switzerland) has shown remarkable efficacy in the treatment of chronic myelogenous leukemia (CML), with a high proportion of patients achieving complete cytogenetic responses (CCRs). However, it is not clear whether remissions will be durable and whether imatinib mesylate can eliminate the malignant primitive progenitors in which the disease arises. We investigated whether residual BCR/ABL+ hematopoietic progenitors were present in patients who achieved CCRs with imatinib mesylate treatment. CD34+ progenitor cells were selected from bone marrow mononuclear cells (MNCs) and analyzed for the presence of the BCR/ABL fusion gene by fluorescence in situ hybridization (FISH). CD34+ cells were also plated in committed progenitor (colony-forming cell, or CFC) and primitive progenitor (long-term bone marrow culture-initiating cell, or LTCIC) cultures and resulting colonies analyzed for the presence of BCR/ABL+ cells by FISH. Using these assays, residual BCR/ABL+ progenitors were detected in all patients studied. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis demonstrated increased levels of BCR/ABL mRNA in CD34+ cells compared with total MNCs. Evaluation of samples collected at different time points demonstrated persistence of BCR/ABL+ progenitors despite continued treatment with imatinib mesylate. Our results indicate that inhibition of BCR/ABL tyrosine kinase activity by imatinib mesylate does not eliminate malignant primitive progenitors in CML patients. Patients in CCR with imatinib mesylate treatment need to be followed carefully to assess for risk of relapse. © 2003 by The American Society of Hematology.