American Indians (AI) face significant disparities in HIV/STI morbidity and mortality, and historical, structural, interpersonal, and individual level barriers stymie prevention efforts. The objective of this paper is to examine barriers to HIV/STI prevention among reservation-based AI. We conducted face-to-face qualitative interviews with 17 reservation-based AI community leaders and community members in Southern California on HIV/STI knowledge and attitudes and barriers to prevention. The disruption of traditional coping mechanisms and healing processes were compromised by historical trauma, and this allowed stigmas to exist where they did not exist before. This impacted access to healthcare services and trust in medicine, and is linked to individuals adopting negative coping behaviors that confer risk for HIV/STI transmission (e.g., substance use and sexual behaviors). Most of the participants reported that HIV/STIs were not discussed in their reservation-based communities, and many participants had a misperception of transmission risk. Stigma was also linked to a lack of knowledge and awareness of HIV/STI’s. Limited available services, remoteness of communities, perceived lack of privacy, and low cultural competency among providers further hindered the access and use of HIV/STI prevention services. These findings highlight the need to address the historical, structural, and interpersonal factors impacting individual-level behaviors that can increase HIV/STI transmission among reservation-based AIs. Prevention work should build on community strengths to increase HIV/STI knowledge, reduce stigma, and increase access to preventative care while using culturally grounded methodologies.