We examined the relationship between patient literacy level and self-reported HIV medication adherence, while estimating the mediating roles of treatment knowledge and self-efficacy on this relationship.Structured patient interviews with a literacy assessment, supplemented by medical chart review, were conducted among 204 consecutive patients receiving care at infectious disease clinics in Shreveport, Louisiana and Chicago, Illinois. Literacy was measured using the Rapid Estimate of Adult Literacy in Medicine (REALM), while the Patient Medication Adherence Questionnaire (PMAQ) was used to assess medication self-efficacy and adherence to antiretroviral regimens in the past 4 days.Approximately one-third of patients (30.4%) were less than 100% adherent to their regimen, and 31.4% had marginal to low literacy skills. In multivariate analyses, low literate patients were 3.3 times more likely to be non-adherent to their antiretroviral regimen (p < 0.001). Patients' self-efficacy, but not knowledge, mediated the impact of low literacy on medication adherence (AOR 7.4, 95% CI 2.7-12.5).While low literacy was a significant risk factor for improper adherence to HIV medication regimens in our study, self-efficacy mediated this relationship.Comprehensive intervention strategies that go beyond knowledge transfer may be needed to address self-efficacy among patients across all literacy levels to be successful in the management of difficult medication schedules.