Adherence to antiretroviral (ARV) therapy for HIV infection is critical for maximum benefit from treatment and for the prevention of HIV-related complications. There is evidence that many factors determine medication adherence, including adherence self-efficacy (confidence in one's ability to adhere) and relations with health care providers. However, there are no studies that examine how these two factors relate to each other and their subsequent influence on HIV medication adherence. The goal of the current analysis was to explore a model of medication adherence in which the relationship between positive provider interactions and adherence is mediated by adherence self-efficacy. Computerized self-administered and interviewer-administered self reported measures of medication adherence, demographic and treatment variables, provider interactions, and adherence self-efficacy were administered to 2765 HIV-infected adults on ARV. Criteria for mediation were met, supporting a model in which adherence self-efficacy is the mechanism for the relationship between positive provider interactions and adherence. The finding was consistent when the sample was stratified by gender, race, injection drug use history, and whether the participant reported receipt of HIV specialty care. Positive provider interactions may foster greater adherence self-efficacy, which is associated with better adherence to medications. Results suggest implications for improving provider interactions in clinical care, and future directions for clarifying interrelationships among provider interactions, adherence self-efficacy, and medication adherence are supported.