OBJECTIVES: Prior literature showed that people holding fatalistic beliefs, defined as events are controlled by external forces and humans are powerless to influence them, are less likely to engage in cancer preventive behavior such as smoking and exercising. The study aimed to assess rural-urban difference in fatalistic beliefs about cancer prevention.  METHODS: The Health Information National Trend Survey (HINTS)–2007 data was used in this study; it is conducted biennially by National Cancer Institute to collect cancer related information from non-institutionalized adult population. Three fatalistic beliefs were captured in the database: 1) it seems like everything causes cancer; 2) there are so many different recommendations about preventing cancer, it is hard to know which ones to follow; and 3) there is not much you can do to lower your chances of getting cancer. All survey participants were included in the cohort. Multivariable logistic regression was used to assess rural-urban differences in three fatalistic beliefs adjusting for age, gender, race, region, education, employment status, income, health insurance, marital status, cancer history and cancer seeking information. All analyses were carried out using jackknife weights to account for survey design enabling us to extrapolate results at national level.  RESULTS: Of 7674 participants, 54.59% agreed that everything causes cancer, 76.7% agreed that it’s hard to know which recommendations to follow and 28.29% agreed that they cannot do much to lower chances of getting cancer. Compared to urban residents, rural residents were 35% (OR: 1.35; 95% CI: 1.12-1.60), 36% (OR: 1.36; 95% CI: 1.10-1.68) and 31% (OR: 1.31; 95% CI: 1.07-1.60) more likely to hold fatalistic beliefs (i), (ii) and (iii), respectively.  CONCLUSIONS: A substantial proportion of Americans hold fatalistic beliefs about cancer prevention. Programs or interventions should be specifically designed for rural population to reduce fatalistic beliefs that might improve cancer prevention behaviors.