There are three types of the root canal sealers commonly used in clinical applications. They are calcium hydroxide base (Sealapex), zinc oxide-eugenol base (Canals), and epoxy-resin base (AH Plus). Elutable substances and degradation products from root canal sealers may gain access to periodontal tissue in a number of ways. The purpose of the present study was to evaluate the biologic effects of the root canal sealers on human oral cancer cell line (OC2). The tetrazolium bromide (MTT) assay was to evaluate the cell's survival rate. The DNA electrophoresis was used to evaluate the OC2 cell's DNA damage. The results demonstrated that the above root canal sealers' survival rates are in dose-dependent increase (p < 0.05). The toxicity of fresh mix group is higher than that of the mixed after 24h group. DNA fragmentation assay of sealer treated OC2 cells shows a smear layer pattern on the electrophoresis gel. There is no DNA damage found. The toxicity that regulated the cell death is not by the apoptic change of cells.