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. We here show, that expression of par-4 in T-lymphoblastic Jurkat cells i) considerably increases TRAIL-induced apoptosis; ii) enforces cleavage of c-FlipL and the subsequent activation of the initiator caspases-8 and -10; iii) does not alter expression of the Bcl-2 family members Bax and Bak; iv) does not enhance the disruption of mitochondrial membrane potential; v) promotes down-regulation the inhibitor-of-apoptosis proteins cIAP-1, cIAP-2, XIAP and survivin; vi) concomitantly augments activation of the executioner caspases-6 and -7. Moreover we prove the crucial role of caspase-8 in par-4-promoted apoptosis by demonstrating that inhibition of caspase-8 considerably reduces TRAIL-induced apoptosis in mock- as well as par-4-transfected Jurkat clones and reverses the described molecular changes. In conclusion, we here provide first evidence that expression of par-4 determines sensitivity to TRAIL-induced lymphocytic cell death and outline the responsible molecular determinants.