Although chewing tobacco, smoking, and alcohol drinking have been suggested as risk factors for oral cancer, no study has examined the relationship between those factors and the risk of erythroplakia, an uncommon but severe oral premalignant lesion. In this study, we have analyzed the effects of chewing tobacco, smoking, alcohol drinking, body mass index, and vegetable, fruit, and vitamin/iron intake on the risk of erythroplakia and explored potential interactions between those factors in an Indian population. A case-control study including 100 erythroplakia cases and 47,773 controls was conducted, as part of an on-going randomized oral cancer screening trial in Kerala, India. The analysis was based on the data from the baseline screening for the intervention group, where the diagnostic information was available. The information on epidemiological risk factors was collected with interviews conducted by trained health workers. The erythroplakia cases were identified by health workers with oral visual inspections, and then confirmed by dentists and oncologists who made the final diagnosis. The odds ratios (OR) and their 95% confidence intervals (CIs) were calculated by the logistic regression model using SAS software. The adjusted OR for erythroplakia was 19.8 (95% CI, 9.8-40.0) for individuals who had ever chewed tobacco, after controlling for age, sex, education, body mass index, smoking, and drinking. The adjusted OR for ever-alcohol-drinkers was 3.0 (95% CI, 1.6-5.7) after controlling for age, sex, education, body mass index, chewing tobacco, and smoking. For ever-smokers, the adjusted OR was 1.6 (95% CI, 0.9-2.9). A more than additive interaction on the risk of erythroplakia was suggested between tobacco chewing and low vegetable intake, whereas a more than multiplicative interaction was indicated between alcohol drinking and low vegetable intake, and between drinking and low fruit intake. We concluded that tobacco chewing and alcohol drinking are strong risk factors for erythroplakia in the Indian population. Because the CIs of interaction terms were wide and overlapping with those of the main effects, only potential interactions are suggested.