Caregiving can have a profound effect on the health of the caregiver, yet research on caregiving among American Indians is limited. The purpose of this study was to examine the influence of caregiving on the health-related quality of life (HRQoL) of American Indians enrolled in the Education And Research Towards Health (EARTH) study. Participants in the EARTH study represented three different tribes in the Northern Plains and Southwestern regions of the United States who completed self-administered, computer-assisted questionnaires between 2003 and 2006. Participants were classified as caregivers if at least one adult relied on them for personal care or as non-caregivers (n = 3,736). Caregivers were further classified according to type; those caring for an adult with unspecified needs (CAU, n = 482) and those caring for an adult with mental or physical difficulties (CAD, n = 295). HRQoL was measured using the mental and physical health component scores of the Medical Outcomes Study 12-item Short-Form Health Survey. Regional differences emerged with regard to caregiver type. Across both regions, non-caregivers reported significantly better mental and physical health than CAD, and the health of participants classified as CAU did not differ from that of non-caregivers. The health of American Indian caregivers depends on the kind of care provided, but detailed measures of caregiving are necessary to understand how caregiving influences health. This has implications for the design of effective interventions in tribal communities. J Am Geriatr Soc 61:1615–1620, 2013.