Systemic administration of Interferon-alpha (IFN-α) enhances survival of CML patients, however, it is associated with deleterious side effects. Gene transfer of IFN-α into CD34+ stem cells represents a novel strategy to achieve long-term expression of IFN-α. IFN-α gene transfer using adenoviral and retroviral vectors was associated with normal proliferation of CD34+ progenitors as measured by CFU-GM and BFU-E assays. Flow Cytometric Analysis revealed no significant difference in cell viability and analysis of mRNA from CD34+ harvested CFU-GM progenitors by RT/PCR demonstrated the expression of human IFN-α mRNA. RIA revealed that IFN-α infected CD34+ cells produced 72.2 ± 15.4 U/ml/106 cells/24 hs compared to 8.3 ± 2.1 and 4.3 ± 1.2 U/ml/106 cells/24 hs in control vector infected and non-infected cells respectively. We evaluated the In Vivo long-term expression of IFN-α gene by transplanting the infected CD34+ cells into severe combined immune deficient (SCID) mice. Engraftment of CD34+ cells infected with IFN-α gene in NOD/SCID mice was successful for 30 days. Next, we studied the effects of local IFN-α expression on the cellular adhesion molecules, VLA-4, Mac-1, ICAM-1, and L-Selectin in K562 cells and human umbilical endothelial vein cells. K562 cells infected with IFN-α gene showed significantly higher levels of VLA-4, Mac-1 and ICAM-1. We conclude that viral expression of IFN-α gene may provide feasible approach to enhance stem cells engraftment in bone marrow transplantation.