Smoking is the leading cause of preventable death in the United States and has been linked to several dire health consequences including cancer and cardiovascular disease. However, knowledge of the associated risks of tobacco use may not be evenly distributed within the population. We analyzed data from the National Cancer Institute's Health Information National Trends Survey (HINTS, 2003) to characterize current knowledge of cancer prevention and smoking risk in the adult U.S. population and to identify associated sociodemographic, smoking status, and geographic factors. To account for the complex survey design of HINTS, SUDAAN was used to calculate population estimates and confidence intervals. Geographic Information System (GIS) isopleth maps were generated to examine smoking behavior and knowledge. Females, non-Hispanic Whites, those with higher incomes, and former smokers (compared with current smokers) were more likely to reject smoking myths. More accurate smoking risk beliefs were reported by respondents with some college (OR = 1.76) and college degrees (OR = 2.13) compared with those with less than a high school education. Former smokers (OR = 2.53) and never-smokers (OR = 3.26) reported more accurate risk beliefs than current smokers. Knowledge of lung cancer mortality was lower among females (OR = 0.38), older adults (OR age 65-79 = 0.69; OR age 80+ = 0.48), and non-Hispanic Blacks (OR = 0.64). GIS analyses revealed lower knowledge of smoking risk and higher tobacco use in the regions with higher tobacco production and higher tobacco-related mortality. Disparities in tobacco-related knowledge, morbidity, and mortality underscore the need for continued development and delivery of effective prevention and treatment interventions to reduce the population burden of tobacco-related disease.