High concentration of fetal hemoglobin (HbF) of above 1% of the total hemoglobin, is a well established feature of patients with hematological and solid tumors.As such, HbF has been considered an indirect tumor marker, whose synthesis is favored, under conditions of malignancy, by cells of erythroid lineage.However, we assume that HbF is not only such an indirect marker, but also a potential direct marker of malignant, white blood cells (WBC).Our assumption is supported by accumulating evidences about spontaneous HbF genes expression, in leukemia cell lines and by our immunohistochemically detection of HbF in morphologically recognized WBC of leukemia patients.In leukemic cell lines models, HbF was upregulated at a very early developmental stage (CD34+, CD19-,CD2-), indicating that marking malignant WBC by HbF may have important clinical implications in the early detection of the disease and in monitoring response to therapy, where tumor cells are sparse.Another aspect, deserving investigation, is the involvement of HbF expression, in malignant WBC differentiation.HbF marked erythroid differentiation in the leukemic cell line K562 is considered as opposed to leukemic transformation, and drags inducing such differentiation have been proposed as anti tumor agents.All this evidence impose the interesting question whether the same differentiation involvement of HbF expression, does take place in the leukemic bone marrow, in which it may confer important therapeutic and prognostic implications.In order to evaluate the significance of HbF, as a direct marker in leukemia patients, we have recently elaborated a simple and efficient immunohistochemical protocol of staining those cells in bone marrow smears of 19 AML patients and in WBC concentrated peripheral blood smears of 19 CLL patients, treated by anti tumor therapeutics.In parallel we also used the same method for staining of HbF positive and HbF negative cell lines.The cells were permeated for the anti-HbF antibody, then fixed and stained by the peroxidase labled avidin-biotin method.Each sample was titrated for HbF concentration by using two fold dilution of the antibody, 1∶200, 1∶400, 1∶800 and 1∶1600.For confirming the results we used a control of the same antibody diluted 1∶400, after absorbing it with HbF.Most of the cells (100-75%) were HbF positive, with morphology ofmyeloid or lymphoid lineages.In order to evaluate the clinical implication of that method, our purpose is to use it as reciprocated by biochemical measurements of HbF and in parallel comparing the results to the records of the patients.