Despite dramatic advances in adjuvant therapies, patients with malignant glioma face a bleak prognosis. Since many adjuvant therapies seek to induce glioma apoptosis, strategies that lower thresholds for the induction of apoptosis may improve patient outcomes. Therefore, elucidation of the biological mechanisms that underlie resistance to current therapies is needed to develop new therapeutic strategies. Here, we propose a novel mechanism of pro-apoptotic effect induced by a pharmacological Peroxisome Proliferator-activated Receptor-gamma (PPARgamma) agonist, Troglitazone, that facilitates caspase signaling in human glioma cells. Troglitazone activates Protein Tyrosine Phosphatase (PTP)-1B, which subsequently reduces phospho-tyrosine-705 STAT3 (pY705-STAT3) via a PPARgamma-independent pathway. Reduction of pY705-STAT3 in glioma cells caused down-regulation of FLICE-inhibitory protein (FLIP) and Bcl-2. Furthermore, Troglitazone induced Serine-392-phosphorylation of p53 via a PPARgamma-dependent pathway and up-regulation of Bax in a p53-wild-type glioma. When given with TRAIL or caspase-dependent chemotherapeutic agents, such as Etoposide and Pacritaxel, Troglitazone exhibited a synergistic effect by facilitating caspase-8/9 activities. A PPARgamma antagonist, GW9662, did not block this effect, although a PTP inhibitor (PTPI) abrogated it. Knockdown of STAT3 by STAT3-siRNA negated the inhibitory effect of PTPI on Troglitazone, indicating that Troglitazone uses a STAT3-inactivation mechanism that makes caspase-8/9 activities susceptible to cytotoxic agents in glioma cells, and that PTP1B plays a critical role in the down-regulation of activated-STAT3, as well as FLIP and Bcl-2. When taken with caspase-dependent anti-neoplastic agents, Troglitazone may be a promising drug for use against malignant gliomas because it facilitates the caspase cascade, thereby lowering thresholds for the apoptosis induction of glioma cells.