In a community-based sample of urban American Indian and Alaska Native adults, 25 lesbian, gay, bisexual, and two-spirit participants were compared with 154 heterosexual participants with respect to sociodemographic characteristics, Native, cultural participation, trauma, physical and mental health, and substance use. Compared with their heterosexual counterparts, two-spirit participants reported higher rates of childhood physical abuse and more historical trauma in their families, higher levels of psychological symptoms, and more mental health service utilization. Two-spirit participants reported differences in patterns of alcohol use and were more likely to have used illicit drugs other than marijuana. Discussion and recommendations for health promotion interventions and future research are presented in consideration of an "indigenist" health model and the multiple minority status of two-spirit people.