There is now substantial evidence that imatinib may affect immune responses, especially those mediated by T lymphocytes. Fas (CD95/Apo-1), a cell death receptor, is a key regulator of the immune system. We have explored the consequences of treatment on the Fas system in chronic myeloid leukemia patients treated with imatinib. In comparison with healthy controls, we found not only a mild blood lymphopenia but also impairment of phytohemagglutinin activation in CD4Fas and CD8Fas lymphocytes of imatinib-treated patients. Moreover, these lymphocyte populations were more sensitive to FasL-induced cell death in relation to an increase in Fas expression at the cell surface. Taken together, these results reveal the role of Fas receptor in the lymphopenia observed in patients treated with imatinib, with potential deleterious consequences on antileukemic responses against this immunogenic hematological malignancy.