Lung cancer rates in Appalachian Kentucky are almost twice national rates; colorectal cancer rates are also elevated. Although smoking prevalence is high, it does not explain all excess risk. The area is characterized by poverty, low educational attainment, and unemployment. Coal production is a major industry. Pyrite contaminants of coal contain established human carcinogens, arsenic (As), chromium (Cr), and nickel (Ni). We compared biological exposure to As, Cr, and Ni for adults living in Appalachian Kentucky with residents of Jefferson, a non-Appalachian, urban county. We further compared lung and colon cancer rates, demographics, and smoking prevalence across the study areas. Toenail clipping analysis measured As, Cr, and Ni for residents of 23 rural Appalachian Kentucky counties and for Jefferson County. Reverse Kaplan-Meier statistical methodology addressed left-censored data. Appalachian residents were exposed to higher concentrations of As, Cr, and Ni than Jefferson County residents. Lung cancer incidence and mortality rates in Appalachia are higher than Jefferson County and elsewhere in the state, as are colorectal mortality rates. Environmental factors may contribute to the increased concentration of trace elements measured in residents of the Appalachian region. Routes of human exposure need to be determined.