AIMS: To report a study of the relationship between functional health literacy and medication adherence, as mediated by medication-taking self-efficacy, while controlling for the effect of key demographic variables (such as race, income and level of education). BACKGROUND: Medication adherence is critical to successful HIV/AIDS self-management. Despite simplified regimens and the availability of tools to assist with medication-taking, adherence remains a challenge for many people living with HIV/AIDS. DESIGN: Cross-sectional, secondary analysis. METHODS: Data for this study of 302 adults living with HIV/AIDS who were taking antiretroviral medications were collected from January 2004-December 2007. Medication adherence was measured using electronic event monitors. Bivariate analyses and stepwise regression were conducted to examine the associations among functional health literacy, medication-taking self-efficacy and HIV medication adherence. RESULTS: Overall, functional health literacy was much higher than expected; however, adherence in this sample was sub-optimal. Higher medication-taking self-efficacy was associated with higher medication adherence; however, functional health literacy was not significantly related to either medication adherence or self-efficacy beliefs. Hence, medication-taking self-efficacy did not mediate the relationship between functional health literacy and medication adherence. CONCLUSIONS: Medication adherence continues to be an issue for people living with HIV/AIDS. Additional research is needed to understand the disparate findings related to functional health literacy and medication adherence in this and other studies examining this association.