Introduction <p>American Indian and Alaska Native (AI/AN) adults experience type 2 diabetes (T2DM) at twice the rate of non-Hispanic White adults in the United States. Despite the importance of medication adherence for T2DM management, research in this area among AI/ANs is sparse, especially within the context of a commercial health care system. We sought to identify factors associated with medication adherence among AI/AN adults with T2DM and examined the relationship of adherence with glycemic control (hemoglobin A1C).</p> Methods <p>This cross-sectional study was conducted with patients from a commercial healthcare system. Data stemmed from online surveys completed by participants, paired with data from participants’ electronic health records (EHRs). The World Health Organization Multidimensional Adherence Model was used to select potentially significant predictors of adherence (social determinants of health, patient-provider relationship, diabetes-related comorbidities, medication regimen complexity, outcome expectancies and self-efficacy). Linear regression and a mediator model were used.</p> Results <p>The sample included <i>n</i> = 88 participants with an average A1C = 7.7. The multiple regression model revealed only age and self-efficacy as significant predictors of medication adherence, explaining 27% of its variability. Medication adherence explained 25% of the variability in A1C. In the mediator model, medication adherence fully mediated the relationship between self-efficacy and A1C.</p> Conclusion <p>Among the many factors potentially related to medication adherence, self-efficacy was the only modifiable factor significantly associated with adherence. System- and individual-level interventions that target enhanced self-efficacy may have a meaningful impact on improved medication adherence and glycemic control.</p>