RNA binding motif protein 15 (RBM15) was originally described as a 5' translocation partner of the MAL gene in t(1;22)(p13;q13)infant acute megakaryocytic leukemia. Although previous investigations have shown that Rbm15 has broad regulatory effects within murine hematopoiesis through modulating Notch-induced transcriptional activation, which plays key roles in leukemogenesis, it is not clear what the functions of RBM15 are in the regulation of hematological malignancies. In the present study, we show that RBM15 expression was significantly increased in patients with blast-crisis chronic myelogenous leukemia (CML) compared with chronic-phase or accelerated-phase disease by real-time reverse transcription-polymerase chain reaction (RT-PCR) assay. To further elucidate the role of RBM15 in CML, we introduced RBM15 small interfering RNA (siRNA) using pSUPER into CML cells. Fluorescence activated cell sorting (FACS), real-time RT-PCR and Western blot were used to study changes in RBM15 expression levels in transduced cells by comparing with control cells. Decreasing RBM15 levels with RNA interference could inhibit the growth and proliferation, block the cell cycle and induce apoptosis in CML cells. Knockdown of RBM15 may also act to inhibit clonogenicity and induce differentiation of CML cells along the myeloid lineage. Our studies also show that the effects of RBM15 on CML cells may be mediated, at least in part, via its effect on Notch signaling. These findings demonstrate that RBM15 does indeed play a critical role in the survival of CML cells, which may have potential application in designing molecular therapies for CML treatment.