Indigenous populations from Australia, Canada, and New Zealand have been found to have a three to eight times higher rate of hospitalization and death associated with infection with the 2009 pandemic influenza A (H1N1) virus. In October, two U.S. states (Arizona and New Mexico) observed a disproportionate number of deaths related to H1N1 among American Indian/Alaska Natives (AI/ANs). These observations, plus incomplete reporting of race/ethnicity at the national level, led to formation of a multidisciplinary workgroup comprised of representatives from 12 state health departments, the Council of State and Territorial Epidemiologists, tribal epidemiology centers, the Indian Health Service, and CDC. The workgroup assessed the burden of H1N1 influenza deaths in the AI/AN population by compiling surveillance data from the states and comparing death rates. The results indicated that, during April 15-November 13, AI/ANs in the 12 participating states had an H1N1 mortality rate four times higher than persons in all other racial/ethnic populations combined. Reasons for this disparity in death rates are unknown and need further investigation; however, they might include a high prevalence of chronic health conditions (e.g., diabetes and asthma) among AI/ANs that predisposes them to influenza complications, poverty (e.g., poor living conditions), and delayed access to care. Efforts are needed to increase awareness among AI/ANs and their health-care providers of the potential severity of influenza and current recommendations regarding the timely use of antiviral medications. Efforts to promote the use of 2009 H1N1 influenza monovalent vaccine in AI/AN populations should be expanded.