The habit of areca quid chewing is wide spread in Taiwan, Southeast Asia and India. Unfortunately, epidemiological studies have shown that the betel quid chewing increases the risk of oral cancer and oral submucous fibrosis. In addition, areca quid chewers have a higher prevalence of periodontal diseases than non-chewers. In this study, the pathological effects of safrole, a main polyphenol compound in Piper betel leaf, were investigated in cultured human gingival fibroblasts (HGFs). The present study demonstrated that safrole was cytotoxic to HGFs in a dose-dependent manner (P<0.05). Safrole also inhibited cell attachment (P<0.05). Control culture exhibited a normal monolayer of long spindle-shaped fibroblast morphology. Safrole-treated HGFs showed a rounding up appearance and detached at the higher concentrations. At the concentration higher than 20 mg/ml, safrole inhibited cell spreading and migration. These results indicate that safrole is a cytotoxic agent to HGFs. Repeated and long-term exposure to safrole could impair the HGFs functions. Areca quid chewers might be more susceptible to destruction of the periodontium and less responsive to regeneration procedure during periodontal therapy.