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A Human Well-Being Index (HWBI) has been developed for the U.S. to help inform and empower decision makers to equitably weigh and integrate human health, socio-economic, environmental and ecological factors to foster sustainability. The integrity of the index structure is designed to be transferable to different U.S. population groups across space, time and demography. This paper presents the applicability and integrity of the HWBI framework using metrics scaled to assess well-being for American Indian Alaska Native (AIAN) and large tribal populations. Potential modifications needed to produce reasonably defensible well-being assessments were identified and HWBIs were calculated for the AIAN population and large tribal groups for the time period covering 2000-2010. Greater than 80 % of the data available for a national AIAN assessment were specific to the target population, while the remaining data were derived from the general U.S. population. Despite the utilization of non-target data, the AIAN well-being signature could still be differentiated from the U.S. HWBI, indicating that the HWBI approach is transferable. As designed, the framework is intended to be used for a variety of spatial scales and demographic groups; however, the degree to which the structure can be utilized is dependent upon the availability and quantity of quality data.