Adenoid cystic carcinoma (ACC) is a common malignant tumor in salivary glands. Unfortunately, current treatment modalities which include surgery, radiation and chemotherapy have limited success rates. To develop new treatment strategies we hypothesized that a cancer-specific apoptotic ligand driven by a tumor specific promoter would specifically induce apoptosis in ACC. To test this concept, we selected tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and the human telomerase reverse transcriptase (hTERT) promoter. The latter is highly active in 85% of human cancer cells while it is mostly inactive in somatic cells. Using immunohistochemistry we confirmed that ACC samples but not normal salivary cells were positive for hTERT. Similar results were also seen in an ACC cell line, SACC-83. We then constructed first generation Ad5 vectors which used the hTERT promoter to drive TRAIL (AdTERT-TRAIL). Transduction of SACC-83, but not of control human embryo-fibrocyte lung (HEL) cells, led to apoptosis as measured by MTT assay and flow cytomerty. We used the SACC-83 cells for a subcutaneous tumor model in vivo. Intratumoral injections of AdTERT-TRAIL (5 x 109 particles/tumor) but not of AdTERT-EGFP or PBS resulted in significant (p < 0.01) reduction in tumor sizes, which demonstrated that the human TRAIL driven by tumor-specific promoter could efficiently induce apoptosis in SACC-83 cells in vitro and in vivo. These results suggest that a novel gene therapy strategy can also be used in the treatment of ACC in the near future.