Since the late nineteenth century, the “Indian” as symbol has been a recurring trope in the art music of Mexico and the United States. Composers in both countries have often turned to representations of Indigenous Peoples as symbolic of nature, spirituality, and/or aspects of the national Self. This article seeks to place James DeMars's opera Guadalupe, Our Lady of the Roses (2008) in the context of two major cultural trends: Indianism in the U.S., and the representation of Mexico by U.S. composers. DeMars's use of Indigenous instruments in Guadalupe, including Mexican pre-Hispanic percussion, and flutes performed by famed Navajo-Ute flutist R. Carlos Nakai, continues the Indianist tradition of associating the Indigenous cultures of both countries with nature, spirituality, and authenticity. Similar associations emerge in the development and reception of both “world music” and the Native American recording industry since the 1980s, as exemplified by Nakai's career. DeMars uses these instruments in combination with Plains Native American features and generic exoticisms to represent both the Mexican Indigenous Peoples and the spiritual message of the opera. The sympathetic treatment of Indigenous cultures in Guadalupe nevertheless exists in tension with their exoticism and Otherness; in this the work is representative of U.S. cultural responses to Mexico stretching back throughout the long twentieth century.