Oral epithelial dysplasia (OED) is a histopathological diagnosis that is associated with an increased risk of oral cancer. The purpose of this case-control study was to measure the association between OED and the use of smoking tobacco and alcoholic beverages. Incident cases of OED (n = 127) were identified through two oral pathology laboratories. Controls, pair-matched 1:1 to cases on age (+/- 5 years), gender, appointment date (+/- 1 year), and surgeon, were identified through the office in which the respective case had been biopsied. Exposure information regarding smoking, drinking, and other potential risk factors was obtained through a standardized telephone interview. Conditional logistic regression was used to calculate measures of association and statistical significance. The odds ratio (OR) for current smoking adjusted for drinking, mouthwash use, denture status, and education was 4.1 (95% confidence interval, 2.1-7.9) relative to never/ex-smokers. The risk of OED increased with increasing levels of smoking and declined following smoking cessation, with ex-smokers of 15+ years demonstrating no excess risk relative to never smokers. Individuals drinking 7+ drinks/week, relative to less than that amount, had over twice the risk of OED (OR, 2.4; 95% confidence interval, 1.2-4.8) after controlling for smoking, mouthwash use, denture status, and education. Adjusted ORs tended to increase with increasing levels of alcohol intake. An exploratory analysis suggests that the joint effect of smoking and drinking may be more than additive as regards the risk of OED. The findings of this case-control study implicate smoking and drinking as important risk factors for OED.