Gingivl overgrowth ( GO ) is a common complication of the usage of phenytoin. It causes severe adverse effect in life quality of patient in maintenance of oral hygiene, language and swallowing. Clinically, periodontal therapy offers removal of the inflammatory component of the GO through scaling and gingival curettage followed by surgical interventions. However, the high recurrence rate of drug-induced gingival overgrowth requires gingivectomy must be repeated periodically. Transforming growth factor β ( TGF-β) is a key regulator associated with pathogenesis of GO. Epithelial-mesenchymal transition (EMT) occurs in wound healing, tumor metastasis and fibrosis. In this study , we found that after 48 hours treatment with phenytoin, the expression of E-cadherin decreased； N-cadherin , vimentin and slug increased in the human gingival epithelial cell (OECM-1,CA9-22) . Pretreatment with TGF-β1 neutralizing antibody, ALK5 in inhibitor SB431542 significantly reduced phenytoin induced p-Smad3 protein production. Furthermore, we found phenytoin increased activated TGF-β levels in OECM-1and CA9-22.Pretreatment of N-acetyl-cystenine ( ROS inhibitor), Diphenylene iodonium (NOX inhibitor), Plumbagin (NOX4 inhibitor ), Apocynine (NOX2 inhibitor), curcumin , EGCG , lovastatin on OECM-1and CA9-22 significantly inhibits production of active form TGF-β1 induce by phenytoin. These results suggested that the increased activated TGF-β levels is regulated by ROS and ROS came from NOX2 and NOX4. Furthermore, curcumin significantly inhibited phenytoin increased TGF-β1 activation in OECM-1and CA9-22.Curcumin could be a potential medicine for prevention and therapy of GO.