The capacity of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) to preferentially induce apoptosis in malignant cells while sparing normal tissues renders it an attractive therapeutic agent. Nevertheless, the molecular determinants governing sensitivity towards TRAIL remain to be defined. Acknowledging the previously demonstrated deregulation of prostate-apoptosis-response-gene-4 (par-4) in ex vivo cells of patients suffering from acute and chronic lymphatic leukemia, we here tested the hypothesis that expression of par-4 influences sensitivity to TRAIL. Evaluating this hypothesis we show, that par-4-transfected T-lymphoblastic Jurkat cells exhibit a considerably increased rate of apoptosis upon incubation with an agonistic TRAIL-antibody as compared to their mock-transfected counterparts. Defining the underlying molecular mechanisms we provide evidence, that par-4 enhances sensitivity towards TRAIL by employing crucial members of the extrinsic pathway. Thus, par-4-overexpressing Jurkat clones show an enforced cleavage of c-Flip(L) together with an increased activation of the initiator caspases-8 and -10. In addition, expression of par-4 enables cells to down-regulate the inhibitor-of-apoptosis proteins cIAP-1, cIAP-2, XIAP and survivin with a concomitantly enhanced activation of the executioner caspases-6 and -7. Supporting the crucial role of caspase-8 in par-4-promoted apoptosis we demonstrate that inhibition of caspase-8 considerably reduces TRAIL-induced apoptosis in par-4 and mock-transfected Jurkat clones and reverses the described molecular changes. In conclusion, we here provide first evidence that expression of par-4 in neoplastic lymphocytes augments sensitivity to TRAIL-induced cell death and outline the responsible molecular mechanisms, in particular the crucial role of caspase-8 activation.