BACKGROUND: Cancer incidence rates vary among American Indian and Alaska Native (AI/AN) populations and often differ from rates among non-Hispanic whites (NHWs). However, the misclassification of race for AI/AN cancer cases in central cancer registries may have led to underestimates of the AI/AN cancer burden in previous reports. METHODS: Cases diagnosed during 1999 through 2004 were identified from population-based cancer registries in the United States. Age-adjusted rates were calculated for the 25 most common sites for AI/ANs and NHWs. To minimize the misclassification of race, cancer registry records were linked with patient registration files from the Indian Health Service (IHS). Analyses were restricted to Contract Health Service Delivery Area (CHSDA) counties and were stratified by IHS region. RESULTS: In CHSDA counties, cancer incidence rates among AI/ANs varied widely by region, whereas rates among NHWs did not. For all cancer sites combined, AI/AN rates were higher than NHW rates among both males and females in the Northern and Southern Plains, and among Alaska Native Females; AI/AN rates were lower than NHW rates in the Southwest, the Pacific Coast, and the East. Lung cancer and colorectal cancer rates for AI/ANs exceeded rates for NHWs in Alaska and the Northern Plains. Rates for stomach, gallbladder, kidney, and liver cancer were higher among AI/ANs than among NHWs overall, in Alaska, in the Plains regions, and in the Southwest. CONCLUSIONS: Regional differences in cancer incidence rates among AI/AN populations were not obvious from nationwide data and highlighted opportunities for cancer control and prevention. It is unlikely that such differences are explained by race misclassification.