American Indian and Alaska Native (AI/AN) youth are more likely to ever have had sex, and to have engaged in sexual activity prior to age 13 compared to all other race groups. It is essential to understand the development of skills to refuse sexual experience in early adolescence in order to reduce disparities associated with early sexual debut among AI/AN youth. Familial, social, and individual factors can act as protective influences on adolescent sexual experience; however, in other settings, research has shown that frequent residential mobility disrupts these protective influences and may increase the likelihood of adolescent sexual activity. AI/AN youth are highly mobile, and, as a result, may be especially vulnerable to increased sexual risk. To date, no prior study has considered the impact of residential mobility on AI/AN youth sexual experience, nor the influence on precursors that reduce initiation of sex. We used data from a longitudinal study of AI/AN youth attending all middle schools from a Northern Plains reservation from 2006-2009 to estimate a structural equation model based on a cultural and age adapted theoretical framework. The tested model included frequent residential mobility as the independent variable and sex refusal self-efficacy as the dependent variable. Mediating variables included factors related to individual risks, psychological well-being, and social supports. Results indicate a direct association between residential mobility and sex refusal self-efficacy (-.29, p = 0.05) and an indirect association mediated by deviant peers (-.08, p = .05). Other mediating variables did not provide insight on the mechanism by which residential mobility influences skills to refuse sexual intercourse among AI/AN youth in early adolescence. Findings provide evidence for an association between residential mobility and precursors to sexual experience suggesting augmenting sexual health interventions for highly mobile youth.