Background: The use of white and red areca nut is indigenous to Southeast Asia. Oral submucous fibrosis is a high risk precancerous condition, with etiological hypothesis of chronic irritant (chewing of betel quid), collagen, genetic or immunological disorder. The aim of the study was to assess the effects of red and white areca nut and betel quid in Wister albino rats. Method: The study was performed on 56 Wister albino rats divided equally into 7 groups. 1 gm of areca nut or quid paste was applied bilaterally on the buccal mucosa on alternate days for 6 months. Applications and subsequent biopsies at 2, 4 and 6 months were done using haematoxylin, eosin and Van Geison's stain for histopathological examination. Results: Keratosis, basal cell hyperplasia, submucosal collagen, vascular change, inflammatory infiltrate were significantly altered in the study group compared to control group (p 0.05). Groups without tobacco showed statistically significant (p 0.05) changes in keratosis, loss of basal layer polarity, basal cell hyperplasia, vascular changes and inflammatory infiltrate compared to the control. Comparison between tobacco groups and control showed statistically significant (p0.05) differences in keratosis, basal cell hyperplasia, submucosal collagen and inflammatory infiltrate. The relative risk (RR) for epithelial dysplastic changes was least in group 2 (1.52) and highest (2.66) in groups 1, 3 and 6. Changes in submucosal collagen showed least RR (1.33) for group 4 and highest (2.66) for group 5. For vascular changes, the least RR (1.5) was seen in group 1 and highest (4.0) in group 3. Conclusion: White variety of arecanut, alone or in combination, revealed more epithelial and connective tissue changes than the red variety. Arecanut, alone or in combination, caused epithelial and submucosal changes; the degree of change increased in combination with slaked lime and tobacco. Keywords: Areca nut, Oral Submucous Fibrosis, OSF, Wister albino rats, Tobacco, Betel quid