Treatment of chronic myelogenous leukemia (CML) with interferon-α frequently results in normalization of peripheral blood counts and, in up to 20% of patients, reestablishment of normal hematopoiesis. We hypothesize that interferon-α may restore normal adhesive interactions between CML progenitors and the bone marrow microenvironment and restore normal growth regulatory effects resulting from these progenitor-stroma interactions. We demonstrate that treatment with interferon-α induces a significant, dose- dependent increase in the adhesion of primitive long-term culture initiating cells and committed colony-forming cells (CFC) from CML bone marrow to normal stroma. Adhesion of CFC seen after interferon-α treatment could be inhibited by blocking antibodies directed at the α4, α5, and β1 integrins and vascular cell adhesion molecule, but not CD44 or intracellular adhesion molecule, suggesting that interferon-α induces normalization of progenitor- stroma interactions in CML. Because FACS® analysis showed that the level of α4, α5, and β1 integrin expression after interferon-α treatment is unchanged, this suggests that interferon-α may restore normal β1 integrin function. Normalization of interactions between CML progenitors and the bone marrow microenvironment may then result in the restoration of normal regulation of CML progenitor proliferation, and explain, at least in part, the therapeutic efficacy of interferon-α in CML.