Periodontal disease (Pd) is characterized by an increased osteoclast resorption and a decreased osteoblast (OB) bone formation. OBs obtained from alveolar bone of Periodontitis patients (Pp) undergo apoptosis in the presence of TNF-related apoptosis-inducing ligand (TRAIL). We studied the intracellular apoptotic pathway induced by TRAIL; TRAIL death (DR4, DRS) and decoy (DcRl, DcR2) receptors expression in Periodontitis patients' OBs (PpOBs), and we measured the concentration of TRAIL in the serum of Pp. We demonstrated that DNA fragmentation and activation of caspase-8 and caspase-3 in PpOBs, following TRAIL stimulation, occurred in shorter time; moreover, a higher amount of both caspases was activated in order to direct OBs. Down-regulation of DcR2 in PpOBs was demonstrated and high TRAIL levels were detected in the serum of Pp. In conclusion, our data suggest that PpOBs are more sensitive to TRAIL-induced apoptosis when compared to the control group. The down-regulation of DcR2 possibly leads to an imbalanced ratio between death and decoy receptors. Our findings highlight a role of TRAIL in the pathogenesis of Pd.Periodontal disease, defined as a plaque-induced inflammation of the periodontal tissues, results in alveolar bone loss supporting the affected teeth and is considered the most frequent cause of tooth loss among adults (1-2). Destruction of the periodontal attachment apparatus, increased bone resorption with loss of crestal alveolar bone, apical migration of the epithelial attachment, and formation of periodontal pockets characterize the disease process (1-8). Bone remodelling is a multi-step and tightly regulated process leading to the coordinated action of bone forming cells, osteoblasts (OBs), and bone resorbing cells, osteoclasts. In the bone microenvironment, the balance between osteoclast and OB activity depends upon the ratio of their proliferation and apoptosis, thus determining the prevalence ofbone formation or resorption. Abnormality in the apoptosis regulation of bone cells can promote osteolytic bone disorders (9-11).TNF-related apoptosis-inducing ligand (TRAIL),