OBJECTIVE: Smokeless tobacco (ST) use remains a prevalent form of tobacco use among certain US populations. The purpose of this paper is to clarify its role in cancer development. METHODS: Using data from a prospective cohort of the US population, we categorized 6,779 subjects 45-75 years of age as ST users or non-ST users. Subjects were further stratified by cigarette smoking status in order to differentiate 'exclusive' ST users (n=414) from never tobacco users (n=2,979). RESULTS: In this cohort, exclusive ST use was not associated with increased incidence of all cancer in males (hazard ratio=0.8, 95% CI: 0.4, 1.6) or females (HR=1.2, 95% CI: 0.7-2.1) or oral cancer (standardized incidence ratio=30, 95% CI: 3, 95). No synergistic effect was observed between ST and cigarette smoking among male combined users (females were not analyzed for combined use) for the major cancers. CONCLUSIONS: In contrast to the well-known deleterious effects of cigarette smoking, ST use did not substantially increase the risk for cancer incidence above that of non-tobacco users, particularly among males. Although the use of tobacco in any form is to be discouraged, our data suggests that cancer risks are much lower from ST use than from cigarette smoking.