According to the Office of Minority Health, an estimated 4.9 million people living in the United States consider themselves American Indian or Alaska Native, either alone or in combination with one or more races/ethnicities. American Indians or Alaska Natives comprise a racial/ethnic group experiencing serious health disparities, with little if any improvement in health outcomes over the past several decades. This study was designed to explore use of the Internet as a health information source among American Indians in the Central Plains region of the United States. The authors recruited 998 Natives in the region from May 2008 to December 2009 at powwows, health fairs, focus groups, career fairs and conferences, and other social and cultural events, and asked them to complete a self-administered survey. Although compared with data from the general population, American Indians or Alaska Natives in this sample may seem to be more frequent Internet users, their use of modern wireless devices is limited, and their use of the Internet to access health information is lower in comparison with the adult U.S. population. Natives living in the Central Plains region face generational differences in general and health-related use of the Internet. Inadequate availability of culturally appropriate health information websites may drive American Indians or Alaska Natives toward search engines and general information websites.