Background Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) is an apoptosis-inducing member of the TNF gene family which triggers apoptotic signals by interaction with its receptors. It has been suggested to be a major contributing factor to tissue degeneration. Objective The present study investigated, through immunohistochemistry, the regional expression of TRAIL and in temporomandibular joint (TMJ) disc of anterior disc displacement with reduction (ADDwR) and without reduction (ADDwoR) patients, to help determine the relationship between TMJ disc displacement and apoptosis. Study design We studied 18 TMJ diseased discs affected by disc displacement without or with reduction and 4 normal TMJ discs. Specimens were processed for immunohistochemistry to evaluate TRAIL and its receptor DR5 expression. Results Disc tissues from internal derangements (both ADDwR and ADDwoR) exhibited a much higher percentage of TRAIL- and DR5-positive cells as well as stain intensity compared with normal tissue though with regional variation according to the portion of the disc. There was a significantly higher percentage of stained cells in the posterior disc attachment compared with the anterior or intermediate bands of both ADDwR and ADDwoR discs for TRAIL and DR5. Conclusions TRAIL and DR5 are overexpressed in displaced human TMJ disc, especially in the posterior disc attachment. These results suggest a possible pivotal role of the TRAIL/DR5 system in TMJ disc degeneration