The interaction between p145^c-KIT and p210^bcr-abl in transduced cell lines, and the selective outgrowth of normal progenitors during long-term culture of chronic myeloid leukemia (CML) cells on stroma deficient in stem-cell factor (SCF) suggests that the response of CML cells to SCF may be abnormal. We examined the proliferative effect of SCF(100 ng/mL), provided as the sole stimulus, on individual CD34⁺ cells from five normal donors and five chronic-phase CML patients. Forty-eight percent of isolated single CML CD34⁺ cells proliferated after 6 days of culture to a mean of 18 cells, whereas only 8% of normal CD34⁺ cells proliferated (mean number of cells generated was 4). SCF, as a single agent, supported the survival and expansion of colony-forming unit–granulocyte-macrophage (CFU-GM) from CML CD34⁺CD38⁺ cells and the more primitive CML CD34⁺CD38⁻ cells. These CFU-GM colonies were all bcr-abl positive, showing the specificity of SCF stimulation for the leukemic cell population. Coculture of CML and normal CD34⁺ cells showed exclusive growth of Ph⁺cells, suggesting that growth in SCF alone is not dependent on secretion of cytokines by CML cells. SCF augmentation of β₁-integrin–mediated adhesion of CML CD34⁺cells to fibronectin was not increased when compared with the effect on normal CD34⁺ cells, suggesting that the proliferative and adhesive responses resulting from SCF stimulation are uncoupled. The increased proliferation may contribute to the accumulation of leukemic progenitors, which is a feature of CML.