The purpose of this study was to characterize the relation between smokeless tobacco use and the risk of all-cause and disease-specific mortality. Using data from the First National Health and Nutrition Examination Survey Epidemiologic Followup Study, the authors assessed the 20-year mortality experience of smokeless tobacco users. Subjects aged 45 years or more at baseline (1971-1975) were categorized as either smokeless tobacco users (n = 1,068) or non-smokeless tobacco users (n = 5,737). Subjects were further stratified by smoking status and gender. Proportional hazard ratios were used to assess associations. After adjustment for confounders, no association between smokeless tobacco use and all-cause (hazard ratio = 1.1, 95% confidence interval (CI): 0.9, 1.3), all cancer (hazard ratio = 1.1, 95% CI: 0.6, 1.9), or all cardiovascular (hazard ratio = 1.1, 95% CI: 0.8, 1.5) mortality was found. There was an increase in all cancer mortality of borderline significance among female smokeless tobacco users (hazard ratio = 1.7, 95% CI: 1.0, 2.8). The lung cancer mortality rate among combined users (smokeless tobacco and cigarettes), based on the rates for exclusive smokeless tobacco users and exclusive smokers, was higher than expected, possibly because of heavier smoking among these subjects. The mortality experience of smokeless tobacco users was not significantly greater than that of non-tobacco users and was appreciably less than that of cigarette smokers. Furthermore, combined use of smokeless tobacco and cigarettes did not increase overall mortality beyond that expected from use of the individual products.