TRAIL receptors are differentially expressed on restricted subpopulations of normal blood cells. In the present study, we investigated the utility of individual TRAIL receptors in evaluating the presence of circulating tumor cells in blood. Patients with chronic myeloid leukemia (CML) carrying the t(9;22) translocation were compared with patients in whom no translocation was detected, with patients with multiple myeloma and with a group of healthy individuals. TRAIL receptor expression was analyzed by RT-PCR in blood mononuclear cells. Blood mononuclear cells of healthy subjects expressed the TRAIL-R1 and TRAIL-R2 death receptors and the TRAIL-R4 decoy receptor while the other decoy receptor TRAIL-R3 was not detectable. This normal expression pattern was also observed in all cases with multiple myeloma and in almost all patients without translocation (42/43; 97.7%). However, in 24/56 (42.9%) of the translocation-positive patients, the expression pattern was completely different. In this group the TRAIL-R4 receptor alone or in combination with TRAIL-R1 disappeared from blood mononuclear cells, while the TRAIL-R2 was expressed at normal level, indicating that the loss of expression is specific for the TRAIL-R4 and TRAIL-R1. This expression pattern was also confirmed by real-time PCR. The differences between the translocation-positive and -negative groups for the TRAIL-R4 and TRAIL-R1 expression were highly significant (p= 0.0001 and p= 0.0004, respectively). However, the differential expression pattern did not correlate with the number of leukemic cells. Our results suggest a correlation between the presence of leukemic cells in circulation and the differential expression pattern of TRAIL receptors in blood mononuclear cells.