Objective: Oral submucous fibrosis (OSF) is a pre-malignant fibrotic lesion of the mouth in areca quid chewers. It is probably a consequence of disturbances in the homeostatic equilibrium between synthesis and degradation of extracellular matrix molecules. Recently, we found that plasminogen activator inhibitor-1 (PAI-1) mRNA and protein were found to be upregulated in OSF (Oral Oncology 2003:367-72). However, the detail molecular mechanism is still remained to be elucidated. Methods: In this study, we performed the genetic analysis of PAI-1in the upstream -675bp of the promoter region between OSF and normal buccal mucosa. PAI-1 genotyping with allele-specific restriction enzyme site analysis was performed in the specimens from 50 OSF and 30 normal buccal mucosa. Chi-square test was used as statistical analysis in this study. Results: There was a single guanosine deletion/insertion 4G/5G polymorphism -675 bp upstream from the start of transcription within the promoter. Our findings suggested that the distribution pattern of PAI-1 promoter were different between OSF and normal buccal mucosa (P< 0.05). It had a high frequency of PAI-1 (4G/4G) genotypes in the OSF group (28%) than those in normal buccal mucosa group (18%). The percentage of 4G/5G from OSF and normal buccal mucosa were 58% and 45%, respectively. In addition, the percentage of 5G/5G from OSF and normal buccal mucosa were 14% and 36%, respectively. Conclusions: We conclude that PAI-1 4G allele, with a higher transcription activity, was more prevalent in OSF. This may be one of the molecular mechanisms associated with an increased risk for OSF. This study was supported by NSC 92-2314-B-040-016.