OBJECTIVES: American Indians/Alaska Natives are underrepresented in clinical trials. Therefore, they must participate in large-scale cancer clinical trials to ensure the generalizability of trial results and improve their access to high-quality treatment. Our goal was to identify factors that influenced participation in cancer clinical trials among American Indians/Alaska Natives. METHODS: An anonymous survey that assessed willingness to participate in a hypothetical cancer clinical trial and how 37 factors influenced their willingness to participate was administered to 112 older American Indian/Alaska Native adults at an annual social event honoring elders. Responses ranged from one (definitely would not participate) to five (definitely would participate). Data were analyzed with ordinal logistic regression. RESULTS: Factors that most strongly increased willingness to participate were having a lead researcher of Native descent, having a study physician with experience treating American Indians/Alaska Natives, personal experience with the cancer being studied, family support for participation, and belief/hope that the study would result in new treatments. Factors that decreased willingness to participate most strongly were living far from the study site and a high risk that confidentiality could be breached. CONCLUSIONS: Our results identify conventional and culturally unique barriers to research participation among older American Indians/Alaska Natives. These data emphasize the need to establish partnerships with Native communities and include American Indian/Alaska Native and culturally competent professionals in research efforts. Of equal importance are disseminating information about clinical trials and recognizing the role of family in decisionmaking in this group.