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Background: Researchers have not been able to examine cancer incidence rates in Appalachia because high-quality data have not been uniformly available across the region. This study is the first to report cancer incidence rates for a large proportion of the Appalachian population and describe the differences in incidence rates between Northern, Central, and Southern Appalachia., Methods: Forty-four states and the District of Columbia provided information for the diagnosis years 2001 through 2003 from cancer registries that met high-quality data criteria. Eleven of 13 states with counties in Appalachia, covering 88% of the Appalachian population, met these criteria; Virginia and Mississippi were included for 2003 only. SEER(*)Stat was used to calculate age-adjusted rates per 100,000 population and 95% gamma confidence limits., Results: Overall, cancer incidence rates were higher in Appalachia than in the rest of the US; the rates for lung, colon/rectum, and other tobacco-related cancers were particularly high. Central Appalachia had the highest rates of lung (men: 143.8; women: 75.2) and cervical cancer (11.2)-higher than the other 2 regions and the rest of the US. Northern Appalachia had the highest rates for prostate, female breast, and selected other sites, and Southern Appalachia had the lowest overall cancer incidence rates., Conclusions: Cancer incidence rates in Appalachia are higher than in the rest of the US, and they vary substantially between regions. Additional studies are needed to understand how these variations within Appalachia are associated with lifestyle, socioeconomic factors, urban/rural residence, and access to care., (2007 American Cancer Society)