Oral cancer is one of the most common cancers in the world, with two-thirds of the cases occurring in developing countries. While cohort and nested case-control study designs offer various methodological strengths, the role of tobacco and alcohol consumption in the etiology of oral cancer has been assessed mainly in case-control studies. The role of tobacco chewing, smoking and alcohol drinking patterns on the risk of cancer of the oral cavity was evaluated using a nested case-control design on data from a randomized control trial conducted between 1996 and 2004 in Trivandrum, India. Data from 282 incident oral cancer cases and 1410 matched controls were analyzed using multivariate conditional logistic regression models. Tobacco chewing was the strongest risk factor associated with oral cancer. The adjusted odds ratios (ORs) for chewers were 3.1 (95% confidence interval (CI)=2.1-4.6) for men and 11.0 (95%CI=5.8-20.7) for women. Effects of chewing pan with or without tobacco on oral cancer risk were elevated for both sexes. Bidi smoking increased the risk of oral cancer in men (OR=1.9, 95%CI=1.1-3.2). Dose-response relations were observed for the frequency and duration of chewing and alcohol drinking, as well as in duration of bidi smoking. Given the relatively poor survival rates of oral cancer patients, cessation of tobacco and moderation of alcohol use remain the key elements in oral cancer prevention and control.