To investigate the role of tissue factor (TF) in chemotherapeutic reagent — induced apoptosis on human glioblastoma and explore its mechanism. The expression of TF was examined by Western blotting. The cytotoxicity of doxorubicin was determined by WST assay. The activation of Caspase-3 and PARP induced by adoxorubicin were tested by Western blotting. Human glioblastoma cell line U373MG expressed high level of TF while LN-229 was with low-TF level. The chemotherapeutic reagent doxorubicin revealed stronger cytotoxic effect on high-TF U373MG cells than low-TF LN-229 cells. Enforced strong expression of TF was achieved by transfection of TF-pcDNA3 combinant on LN-229 cells in a dose-dependent manner. Enforced TF expression in transfected LN-229 cells not only impaired the doxorubicin-induced cleavage of Caspase-3 and PARP, but also inhibited the cytotoxic effect of doxorubicin. Furthermore, activation of Akt was strong in high-TF U373MG cells but weak in low-TF LN-229 cells. Incubation of factor VII (FVII) with enforced TF-expressing LN-229 cells increased the phosphorylation of Akt in a time-dependent manner. These results suggest that over-expression of TF on glioblastoma could inhibit doxorubicin-induced apoptosis. Interaction of FVII and TF activates the downstream PI3K/Akt pathway. Tumor-derived over-expression of TF might play a role in chemotherapy resistance in glioblastoma, at lest in part, by activating PI3K/Akt-mediated survival and anti-apoptotic mechanism through the interaction of TF/FVII signaling.