Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/APO2L) is a novel member of the tumor necrosis factor cytokine family and a potent inducer of apoptosis in tumor cells. TRAIL is expressed in most normal human cells and tissues, including peripheral blood leukocytes, spleen, lung and prostate. However, TRAIL expression in human neoplasms is largely unknown. In this study, we investigated whether TRAIL and its receptors are expressed in human oral squamous cell carcinomas (HOSCCs) or HOSCC cell lines (HSC-2, HSC-3, HSC-4, Ca9-22 and KB) and whether these cells are sensitive to TRAIL-induced apoptosis. TRAIL and its receptor transcripts and proteins were detected in all HOSCC cell lines. A cell viability (MTT) assay performed after exposure to recombinant human (rh) TRAIL for 16 h showed that KB cells were the most sensitive. Immunohistochemical examinations for TRAIL expression were also carried out in a total of 50 HOSCC cases with various types of differentiation. In 17 of 27 WHO Grade 1 SCCs, the tumor invasive areas with keratinization showed diffuse and moderate TRAIL expression. In 6 of 20 WHO Grade 2 SCCs, TRAIL expression was slightly to moderately detected. In 1 of 3 WHO Grade 3 SCCs, a slight TRAIL expression was observed. Thus, there is considerable heterogeneity of TRAIL expression and susceptibility to TRAIL-induced apoptosis among human oral tumors.