Racial disparities in HIV/AIDS are well established and efforts to understand key factors that may explain these differences are needed. Recent evidence suggests that health literacy may contribute to disparities in health behaviors among African American HIV patients. One component of health literacy, numeracy, is emerging as an important skill for successful self management of medications. We therefore tested whether numeracy mediated the effects of race on medication management among HIV seropositive patients. Results showed that poor management of a simulated HIV medication regimen among African Americans and women was mediated by lower numeracy. Poor medication self-management may be a significant root cause for health disparities in African Americans with HIV/AIDS. Whether African American women may be at particular risk requires further study. Interventions to improve HIV medication self-management through addressing numeracy skills may help to narrow the gap in health disparities among African Americans with HIV/AIDS.