OBJECTIVES: Determine whether colorectal cancer (CRC) rates are disproportionately high in the French-Acadian region (population 1.2 million) of Louisiana, home of the Cajuns, a founder population. METHODS: 2005-2009 cancer incidence rates were stratified by age/race/gender in the 18 Acadian parish region and 9-parish subgroup with higher proportions of French speakers and compared with Louisiana and United States rates. Parishes were identified through language census data. A total of 3,288 CRC cases were identified in the Acadian region and 11,737 in Louisiana. RESULTS: CRC rates in whites and white males in the 18 parishes were statistically significantly higher than both Louisiana and US rates. In the 9 parishes, rates increased further; whites had an incidence of 56.1/100,000, 13% higher than Louisiana (P<0.0003) and 23% higher than US rates (P<0.0001). In white males, incidence was 72.6/100,000, 19% higher than Louisiana (P<0.0002) and 37% higher than US rates (P<0.0001). If the 9-parish regions were considered a "state," white males would have the highest CRC incidence in the United States by 11% (P<0.0175) compared with other white male populations. CONCLUSIONS: CRC rates are among the highest in the United States, increasing with the proportion of French speakers, a marker for the Cajun population. This appears to be the first study identifying a high rate of cancer in a large, regional, US founder population, raising the possibility of a genetic predisposition. Alternatively, an unidentified, robust environmental risk factor may be present. Future studies are needed to identify genetic and/or other risk factors in this population.