Smokeless tobacco (ST) users and nonusers were recruited to evaluate the contribution of various risk factors (ST use, cigarettes, alcohol, and diet) in the development of oral mucosal lesions. Ninety-eight ST users with no lesion, 29 ST users with an oral lesion, and 33 nonusers were enrolled in the study. ST users with lesions, when compared with users with no lesion, were more likely to have used snuff than chewing tobacco (p = 0.01) and to have used more ST (p less than 0.01). Alcohol consumption, dietary intake of beta-carotene, and serum levels of beta-carotene were not related to an increased risk of lesion development. Our findings showed that the only significant risk factor for ST-associated oral lesions was the extent of ST exposure. Of 127 ST users, 29 (22.8%) had an oral lesion at the time of examination. Of these lesions, 23 (79.3%) were hyperkeratotic and 6 (20.7%) were epithelial dysplasia.